POLIVY

5 WARNINGS AND PRECAUTIONS 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 signs and symptoms of infusion site extravasation occur within hours to weeks and may include a sensation of burning, tingling, pain, discomfort, swelling and redness at the site of injection, and can progress to more severe events like blistering, necrosis, ulceration, and tissue damage such as cellulitis. To minimize the risk of extravasation, ensure patent venous access prior to initiating the infusion and closely monitor the infusion site throughout administration for any signs of extravasation. If extravasation occurs, stop the infusion and manage medically. For mild symptoms, the remaining dose may be administered in an alternate limb after establishing patent venous access. For moderate to severe symptoms, the infusion can be restarted in an alternate limb based on the clinical judgment of the treating physician. 5.9 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 ADVERSE REACTIONS 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. 17 0.5 16 0.5 Metabolism and Nutrition Disorders Decreased appetite 17 1.1 14 0.7 Respiratory Disorders Cough 15 0 14 0 Dyspnea 13 0.9 10 0.9 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 [see Clinical Studies (14.2) ] . 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 8 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 8 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 2.6 Includes 1 fatality. Upper respiratory tract infection 13 0 8 0 Investigations Weight decreased 16 2.2 8 2.6 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 9 . 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 9 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 2.6 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 2.6 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 10 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 10 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 2.3 Gastrointestinal Disorders Diarrhea 45 8 Vomiting 27 2.9 General Disorders Fatigue 40 5 Pyrexia 30 2.9 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%)

<table width="85%" ID="Table7"><caption>Table 7 Select Adverse Reactions Occurring in &#x2265;10% of Patients Treated with POLIVY Plus R-CHP in POLARIX</caption><col width="40%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th valign="middle" rowspan="2" align="center" styleCode="Lrule Rrule">Adverse Reactions by Body System</th><th colspan="2" styleCode="Rrule">POLIVY + R-CHP n = 435</th><th colspan="2" styleCode="Rrule">R-CHOP n = 438</th></tr><tr><th align="center" styleCode="Lrule Rrule">All Grades, %</th><th styleCode="Rrule">Grade 3&#x2013;4, %</th><th styleCode="Lrule Rrule">All Grades, %</th><th styleCode="Rrule">Grade 3&#x2013;4, %</th></tr></thead><tfoot><tr><td colspan="5" align="left" valign="top">The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Blood and Lymphatic System Disorders</content><footnote ID="Tb6ft1">Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes.</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lymphopenia</td><td styleCode="Rrule">80</td><td styleCode="Rrule">44</td><td styleCode="Rrule">77</td><td styleCode="Rrule">44</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">68</td><td styleCode="Rrule">14</td><td styleCode="Rrule">67</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">60</td><td styleCode="Rrule">39</td><td styleCode="Rrule">60</td><td styleCode="Rrule">42</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">32</td><td styleCode="Rrule">8</td><td styleCode="Rrule">33</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Febrile neutropenia<footnote>Febrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis.</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">15</td><td styleCode="Rrule">9</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content><footnoteRef IDREF="Tb6ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Creatinine increased</td><td styleCode="Rrule">66</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">64</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Aspartate aminotransferase increased</td><td valign="middle" styleCode="Rrule">26</td><td valign="middle" styleCode="Rrule">0.7</td><td valign="middle" styleCode="Rrule">23</td><td valign="middle" styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alanine aminotransferase increased</td><td valign="middle" styleCode="Rrule">25</td><td valign="middle" styleCode="Rrule">1.4</td><td valign="middle" styleCode="Rrule">27</td><td valign="middle" styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alkaline phosphatase increased</td><td valign="middle" styleCode="Rrule">23</td><td valign="middle" styleCode="Rrule">0</td><td valign="middle" styleCode="Rrule">22</td><td valign="middle" styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Uric acid increased</td><td styleCode="Rrule">19</td><td styleCode="Rrule">18</td><td styleCode="Rrule">17</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight decreased</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral neuropathy<footnote>At last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY + R-CHP arm and in 33% in the R-CHOP arm.</footnote>^,<footnote>Peripheral neuropathy includes all terms containing &quot;neuropathy&quot;, neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia.</footnote></td><td styleCode="Rrule">53</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">54</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Altered taste</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">42</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">37</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">31</td><td styleCode="Rrule">3.9</td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">29</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Mucositis<footnote>Mucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration.</footnote></td><td styleCode="Rrule">22</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote>Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms.</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">37</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">38</td><td styleCode="Rrule">3.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">16</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Edema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling.</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infusion-related reaction<footnote>Infusion related reaction is reflective of the combination regimen due to same-day administration.</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">16</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alopecia</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote>Rash includes rash, dermatitis, and related terms.</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal pain<footnote>Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain.</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection<footnote>Upper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections.</footnote></td><td valign="middle" styleCode="Rrule">17</td><td valign="middle" styleCode="Rrule">0.5</td><td valign="middle" styleCode="Rrule">16</td><td valign="middle" styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">17</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.9</td></tr></tbody></table>

<table width="75%" ID="Table8"><caption>Table 8 Adverse Reactions Occurring in &gt;10% of Patients with Relapsed or Refractory DLBCL and &#x2265;5% More in the POLIVY Plus Bendamustine and Rituximab Product Group in Study GO29365</caption><col width="40%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" valign="middle" align="center">Adverse Reactions by Body System</th><th styleCode="Rrule Botrule" colspan="2">POLIVY + BR n = 45</th><th styleCode="Rrule Botrule" colspan="2">BR n = 39</th></tr><tr><th styleCode="Lrule Rrule" align="center">All Grades, %</th><th styleCode="Rrule">Grade 3 or Higher, %</th><th styleCode="Rrule">All Grades, %</th><th styleCode="Rrule">Grade 3 or Higher, %</th></tr></thead><tfoot><tr><td align="left" colspan="5">The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">49</td><td styleCode="Rrule">42</td><td styleCode="Rrule">44</td><td styleCode="Rrule">36</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">49</td><td styleCode="Rrule">40</td><td styleCode="Rrule">33</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">47</td><td styleCode="Rrule">24</td><td styleCode="Rrule">28</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lymphopenia</td><td styleCode="Rrule">13</td><td styleCode="Rrule">13</td><td styleCode="Rrule">8</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral neuropathy</td><td styleCode="Rrule">40</td><td styleCode="Rrule">0</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">38</td><td styleCode="Rrule">4.4</td><td styleCode="Rrule">28</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">18</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infusion-related reaction</td><td styleCode="Rrule">18</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">33</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia</td><td styleCode="Rrule">22</td><td styleCode="Rrule">16<footnote>Includes 2 fatalities.</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">2.6<footnote>Includes 1 fatality.</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight decreased</td><td styleCode="Rrule">16</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypokalemia</td><td styleCode="Rrule">16</td><td styleCode="Rrule">9</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoalbuminemia</td><td styleCode="Rrule">13</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"> Hypocalcemia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="75%" ID="Table9"><caption>Table 9 Select Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and &#x2265;5% More in the POLIVY Plus Bendamustine and Rituximab Product Group</caption><col width="34%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="17%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" valign="middle" align="center">Laboratory Parameter<footnote>Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown.</footnote></th><th styleCode="Rrule Botrule" colspan="2">POLIVY + BR n = 45</th><th styleCode="Rrule Botrule" colspan="2">BR n = 39</th></tr><tr><th styleCode="Lrule Rrule" align="center">All Grades, (%)</th><th styleCode="Rrule">Grade 3&#x2013;4, (%)</th><th styleCode="Rrule">All Grades, (%)</th><th styleCode="Rrule">Grade 3&#x2013;4, (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Hematologic</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lymphocyte count decreased</td><td styleCode="Rrule">87</td><td styleCode="Rrule">87</td><td styleCode="Rrule">90</td><td styleCode="Rrule">82</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutrophil count decreased</td><td styleCode="Rrule">78</td><td styleCode="Rrule">61</td><td styleCode="Rrule">56</td><td styleCode="Rrule">33</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hemoglobin decreased</td><td styleCode="Rrule">78</td><td styleCode="Rrule">18</td><td styleCode="Rrule">62</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Platelet count decreased</td><td styleCode="Rrule">76</td><td styleCode="Rrule">31</td><td styleCode="Rrule">64</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Creatinine increased</td><td styleCode="Rrule">87</td><td styleCode="Rrule">4.4</td><td styleCode="Rrule">77</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Calcium decreased</td><td styleCode="Rrule">44</td><td styleCode="Rrule">9</td><td styleCode="Rrule">26</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> SGPT/ALT increased</td><td styleCode="Rrule">38</td><td styleCode="Rrule">0</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> SGOT/AST increased</td><td styleCode="Rrule">36</td><td styleCode="Rrule">0</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lipase increased</td><td styleCode="Rrule">36</td><td styleCode="Rrule">9</td><td styleCode="Rrule">13</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Phosphorus decreased</td><td styleCode="Rrule">33</td><td styleCode="Rrule">7</td><td styleCode="Rrule">28</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Amylase increased</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td><td styleCode="Rrule">18</td><td styleCode="Rrule">2.6</td></tr><tr><td styleCode="Lrule Rrule"> Potassium decreased</td><td styleCode="Rrule">24</td><td styleCode="Rrule">11</td><td styleCode="Rrule">28</td><td styleCode="Rrule">5</td></tr></tbody></table>