GAZYVA for Previously Untreated Follicular Lymphoma

Transcription

1 NOW APPROVED GAZYVA for Previously Untreated Follicular Lymphoma Studied head-to-head vs rituximab * in stage II bulky, III, and IV patients 1 * GAZYVA and rituximab were each combined with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded. Indication GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma (FL). Select Important Safety Information BOXED WARNINGS: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS.

2 Contents GAZYVA Is the First and Only Approved Therapy That Demonstrated Superior PFS vs rituximab in Previously Untreated FL 1 With chemotherapy * for stage II bulky, III, and IV patients Summary Summary...3 Trial Design....4 GALLIUM Trial Patient Population Results...6 Progression-free Survival (IRC-assessed; primary endpoint) Exploratory Subgroup Analyses: Chemotherapy Regimen Additional Endpoints Safety Profile...12 Adverse Reactions Laboratory Abnormalities Infusion Reactions Dosing...15 Dosing Schedule Recommended Premedication Adjusting Infusions in Case of Infusion Reactions Patient Assistance Information...20 FL In a disease characterized by recurrent relapses and progressively shorter remissions with each relapse, reducing the risk of disease progression or death is an important goal of first-line FL treatment 2 GALLIUM was a Phase III randomized trial that studied over 1,200 previously untreated adult FL patients to determine whether GAZYVA could improve progression-free survival (PFS) vs rituximab when each was combined with bendamustine, CHOP, or CVP and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded 1,3 The GAZYVA based regimen delivered superior PFS vs the rituximab-based regimen as assessed by independent review committee (IRC), reducing patients risk of disease progression or death by 28% (38-month median observation time; HR=0.72; 95% CI, ; P=0.0118; median PFS was not reached in either arm) 1 * GAZYVA and rituximab were each combined with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded. PFS event was defined as disease progression or death. Select Important Safety Information Contraindications GAZYVA is contraindicated in patients with known hypersensitivity reactions (e.g. anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use Warnings and Precautions Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-cd20 antibodies including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and in patients who are HBsAg negative but are hepatitis B core antibody (anti-hbc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-hbc positive, and hepatitis B surface antibody [anti-hbs] positive) Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. Select Important Safety Information Hepatitis B Virus (HBV) Reactivation (cont d) HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti- HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death Screen all patients for HBV infection by measuring HBsAg and anti-hbc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-hbc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA 2 3

3 Trial Design GALLIUM Trial: GAZYVA vs rituximab in Previously Untreated FL 1 With chemotherapy * for stage II bulky, III, and IV patients GAZYVA Was Studied in a Trial of Over 1,200 Patients With Previously Untreated FL 1 With chemotherapy * for stage II bulky, III, and IV patients This Phase III, randomized trial was designed to answer one primary question: In patients with previously untreated FL, did the GAZYVA based regimen deliver superior PFS compared with the rituximab-based regimen? 1 Patients with previously untreated follicular lymphoma (Grades 1-3a, stage III/IV or stage II bulky disease [ 7 cm]) N=1,202 RANDOMIZED 1:1 GAZYVA a + chemotherapy * x 6 or 8 cycles (n=601) rituximab b + chemotherapy * x 6 or 8 cycles (n=601) CR or PR GAZYVA a monotherapy q2 months x 2 years c rituximab b monotherapy q2 months x 2 years c GALLIUM evaluated GAZYVA vs rituximab when each was combined with bendamustine, CHOP, or CVP and followed by GAZYVA or rituximab monotherapy, respectively Percentage of Patients Who Received Each Chemotherapy Regimen 1, * BENDAMUSTINE CHOP CVP 57 % 33 % 10 % Trial Design Primary endpoint: PFS as assessed by Independent Review Committee (IRC) Additional endpoints: Response rates at end of induction (IRC-assessed, assessed by CT ± PET), PFS by chemotherapy regimen (IRC-assessed) * Each investigator site chose CHOP, CVP, or bendamustine; all patients with FL at that site received the chosen chemotherapy for the duration of induction. Patients were stratified by disease characteristics (ie, FLIPI score), chemotherapy regimen, and geographic region at randomization, and the treatment arms were generally balanced with respect to these factors. 3 a Each dose of GAZYVA was 1,000 mg on Days 1, 8, and 15 of Cycle 1, and 1,000 mg on Day 1 of subsequent treatment cycles. 1 b Each dose of rituximab was 375 mg/m 2 administered on Day 1 of each cycle. 3 c In patients achieving a CR or PR at the end of 6-8 cycles, GAZYVA or rituximab monotherapy was administered every 2 months until disease progression or for a maximum of 2 years. 1 * GAZYVA and rituximab were each studied in combination with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded 1,3 : When combined with GAZYVA or rituximab, bendamustine was administered at 90 mg/m 2 /day IV (Days 1-2) for six 28-day cycles, and prednisone or equivalent was administered 100 mg orally (Day 1, Cycle 1) When CHOP was used in combination with GAZYVA or rituximab, cyclophosphamide was administered 750 mg/m 2 IV (Day 1), doxorubicin was administered 50 mg/m 2 IV (Day 1), vincristine was administered 1.4 mg/m 2 IV (maximum = 2 mg) (Day 1), and prednisone (or equivalent prednisolone or methylprednisolone) was administered 100 mg orally on Days 1 to 5 for six 21-day cycles. Subsequently, 2 additional cycles of GAZYVA or rituximab were given without chemotherapy for a total of 8 cycles When CVP was used in combination with GAZYVA or rituximab, cyclophosphamide was administered 750 mg/m 2 IV (Day 1), vincristine was administered 1.4 mg/m 2 IV (maximum = 2 mg) (Day 1), and prednisone (or equivalent prednisolone or methylprednisolone) was administered 100 mg orally on Days 1 to 5 for eight 21-day cycles Each investigator site chose CHOP, CVP, or bendamustine; all patients with FL at that site received the chosen chemotherapy for the duration of induction. At randomization, patients were stratified by disease characteristics (ie, FLIPI score), chemotherapy regimen, and geographic region The GAZYVA and rituximab arms were generally well balanced with respect to demographic factors and baseline disease characteristics 3 Median age in GALLIUM was 59 years (range: years) 97% of patients had an ECOG PS of 0-1 and 3% had an ECOG PS of 2 79% of patients had a FLIPI score >2 Fever, night sweats, or weight loss. 3 Select Patient Characteristics 1,3 34% of patients had at least one B-symptom at baseline 7% of patients had stage II, 35% had stage III, and 56% had stage IV disease 44% of patients had bulky disease ( 7 cm) Select Important Safety Information Hepatitis B Virus (HBV) Reactivation (cont d) In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. Select Important Safety Information Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML, which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML 4 5

4 The GAZYVA Based Regimen * Is the First and Only Approved Therapy That Demonstrated Superior PFS vs the rituximab-based Regimen * in Previously Untreated FL 1 For stage II bulky, III, and IV patients Primary Endpoint: PFS (IRC-assessed) 1 Fewer Patients Progressed or Died With the GAZYVA Based Regimen vs the rituximab-based Regimen 1 With a median observation time of 38 months Primary Endpoint: PFS (IRC-assessed) 1 Results Probability of PFS Medians not yet reached 28 % reduction in the risk of disease progression or death HR= % CI, ; P=0.0118; 38-month median observation time 33 FEWER PATIENTS progressed or died with the GAZYVA based regimen GAZYVA based regimen (n=601) 108 patients progressed or died (18%; 38-month median observation time) rituximab-based regimen (n=601) 141 patients progressed or died (23.5%; 38-month median observation time) HR=0.72, 95% CI, ; P= PFS is defined as survival without progression or death. = approximately 10 patients Results n at risk Time (months) GAZYVA based regimen rituximab-based regimen * GAZYVA and rituximab were each combined with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded. The GAZYVA based regimen delivered superior PFS vs the rituximab-based regimen as assessed by IRC, reducing patients risk of disease progression or death by 28% (38-month median observation time; HR=0.72; 95% CI, ; P=0.0118; median PFS was not reached in either arm). 1 Select Important Safety Information Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Sixty percent of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, and laryngeal edema). Most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. Select Important Safety Information Infusion Reactions (cont d) Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid. Institute medical management for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other lifethreatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy 6 7

5 GALLIUM Studied PFS Overall and by Chemotherapy Subgroup in the Primary and Exploratory Analyses GALLIUM Compared the GAZYVA Based Regimen * and the rituximab-based Regimen * Across Multiple Measures in Previously Untreated FL For stage II bulky, III, and IV patients Results In the primary PFS analysis, the GAZYVA based regimen delivered superior PFS vs the rituximab-based regimen as assessed by IRC, reducing patients risk of disease progression or death by 28% (38-month median observation time; HR=0.72; 95% CI, ; P=0.0118; median PFS was not reached in either arm) 1 Bendamustine CHOP CVP Exploratory Subgroup Analyses: PFS based on chemotherapy (IRC-assessed) 3 Chemotherapy n Events n Events HR * 95% CI G based regimen (n=601) * Unstratified hazard ratio. 38-month median observation time r-based regimen (n=601) ( ) ( ) ( ) Favors G-chemo Favors r-chemo IRC-assessed PFS by chemotherapy subgroup analyses were not powered to demonstrate statistically significant differences between treatment arms. Additional endpoints 1 CT-assessed response rates at the end of induction (IRC-assessed) were similar between arms CT-assessed overall response rates at the end of induction (IRC-assessed) were 91% for the GAZYVA based regimen and 88% for the rituximab-based regimen CT-assessed complete response rates at the end of induction (IRC-assessed) were 28% for the GAZYVA based regimen and 27% for the rituximab-based regimen Additional exploratory analyses 3, Response rates by PET-CT were not controlled for type I error, and the analyses were not powered to demonstrate statistically significant differences between treatment arms In an exploratory analysis, PET-CT response rates at the end of induction (IRC-assessed) were evaluated in 297 patients for the GAZYVA based regimen and 298 patients for the rituximab-based regimen PET-CT assessed overall response rates at the end of induction (IRC-assessed) were 89% for the GAZYVA based regimen and 85% for the rituximab-based regimen (3.3% difference; 95% CI, 2.3 to 8.9) PET-CT assessed complete response rates at the end of induction (IRC-assessed) were 71% for the GAZYVA based regimen and 60% for the rituximab-based regimen (11% difference; 95% CI, 3.9 to 19.4) These analyses are descriptive only. In the GALLIUM trial, PET results were treated as exploratory data and were not used for study treatment decisions. * GAZYVA and rituximab were each combined with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded. Warnings and Precautions: Infections Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. When GAZYVA is administered with chemotherapy followed by GAZYVA monotherapy, Grade 3 to 5 infections have been reported in up to 8% of patients during combination therapy, up to 13% of patients during monotherapy, and up to 8% of patients after treatment. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection In GALLIUM, more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine (117/410 patients, 29%), as compared to GAZYVA plus CHOP or CVP (43/281 patients, 15%). More fatal infections were reported in patients treated with GAZYVA and bendamustine (3%), as compared to GAZYVA plus CHOP or CVP (<1%), including during the monotherapy phase and after completion of treatment Select Important Safety Information Infusion Reactions (cont d) For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. Select Important Safety Information Infusion Reactions (cont d) For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to and during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication 8 9

6 Select Important Safety Information Select Important Safety Information Hypersensitivity Reactions Including Serum Sickness Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediateonset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and tachycardia. Lateonset hypersensitivity diagnosed as serum sickness has also been reported with symptoms that include chest pain, diffuse arthralgia and fever. Hypersensitivity reactions may be difficult to clinically distinguish from infusion related reactions. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occur after previous exposure. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity reactions to GAZYVA, including serum sickness, must not be retreated Tumor Lysis Syndrome (TLS) Tumor lysis syndrome, including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (>25 x 10 9 /L) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with antihyperuricemics (eg, allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA. During the initial days of GAZYVA treatment, monitor the laboratory parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated Infections Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. When GAZYVA is administered with chemotherapy followed by GAZYVA monotherapy, Grade 3 to 5 infections have been reported in up to 8% of patients during combination therapy, up to 13% of patients during monotherapy, and up to 8% of patients after treatment. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection In GALLIUM, more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine (117/410 patients, 29%), as compared to GAZYVA plus CHOP or CVP (43/281 patients, 15%). More fatal infections were reported in patients treated with GAZYVA and bendamustine (3%), as compared to GAZYVA plus CHOP or CVP (<1%), including during the monotherapy phase and after completion of treatment Neutropenia Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during treatment with GAZYVA. Monitor patients with Grade 3 to 4 neutropenia frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Consider administration of granulocyte colony-stimulating factors (GCSF) in patients with Grade 3 or 4 neutropenia Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days) Consider dose delays in the case of Grade 3 or 4 neutropenia. Patients with severe and long lasting (>1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis Thrombocytopenia Severe and life threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chemotherapy. Fatal hemorrhagic events have been reported in patients with NHL treated with GAZYVA in combination with chemotherapy, including during Cycle 1. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors or anticoagulants), especially during the first cycle Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy have not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery Pregnancy There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. GAZYVA is likely to cause fetal B-cell depletion. GAZYVA should be used during pregnancy and/or breastfeeding only if the potential benefit justifies the potential risk to the fetus and/or infant. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child s healthcare providers Geriatric Use Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of patients 65 and over, 63% experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal, while in patients under 65, 43% experienced serious adverse reactions and 13% had an adverse reaction leading to treatment withdrawal. No clinically meaningful differences in efficacy were observed between these patients and younger patients Additional Important Safety Information A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%) Serious adverse reactions occurred in 50% of patients on the GAZYVA arm and 43% of patients on the rituximab product arm. Fatal adverse reactions were reported during treatment in 3% in the GAZYVA arm and 2% in the rituximab product arm, most often from infections in the GAZYVA arm. During treatment and follow-up combined, fatal adverse reactions were reported in 5% of the GAZYVA arm and 4% of the rituximab product arm, with infections and second malignancies being leading causes. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm Neutropenia, infusion related reactions, febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions (incidence 5%) observed more frequently in the GAZYVA arm Throughout treatment and follow-up, the most common adverse reactions (incidence 20%) observed at least 2% more in the GAZYVA arm were infusion related reactions, neutropenia, upper respiratory tract infection, cough, constipation and diarrhea During the monotherapy period, the common adverse reactions (incidence 10%) observed at least 2% more with GAZYVA were upper respiratory infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%) and herpesvirus infection (13%) You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling You may contact the FDA by visiting or calling FDA Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS

7 GALLIUM Trial: Safety Information GALLIUM Trial: Safety Information Common adverse reactions ( 10% incidence and 2% greater in the GAZYVA arm), in patients with previously untreated NHL 1 Common new or worsening laboratory abnormalities ( 10% incidence and 2% greater in the GAZYVA arm) in patients with previously untreated NHL 1 Body System Adverse Reactions a,b GAZYVA + chemotherapy followed by GAZYVA monotherapy (n=691) rituximab + chemotherapy followed by rituximab monotherapy (n=694) Laboratory Abnormalities a GAZYVA + chemotherapy followed by GAZYVA monotherapy (n=691) rituximab + chemotherapy followed by rituximab monotherapy (n=694) All Grades % Grades 3 to 5 % All Grades % Grades 3 to 5 % Injury, Poisoning, and Procedural Complications Infusion-related reactions c Blood and Lymphatic System Disorders Neutropenia d Thrombocytopenia d Infections and Infestations Upper respiratory tract infection Herpesvirus infection Pneumonia Respiratory, Thoracic, and Mediastinal Disorders Cough 35 <1 28 <1 Gastrointestinal Disorders Constipation 32 <1 29 <1 Diarrhea Nervous System Disorders Headache 18 <1 15 <1 Musculoskeletal and Connective Tissue Disorders Arthralgia <1 Psychiatric Disorders Insomnia 15 <1 12 <1 Metabolism and Nutrition Disorders Decreased appetite 14 <1 12 <1 Skin and Subcutaneous Tissue Disorders Alopecia <1 Pruritus 11 <1 9 0 a Includes adverse reactions reported throughout study treatment and follow-up. b Includes grouped preferred terms. c Except where noted, individual events that meet the definition of infusion related reaction are excluded from the table above, as they are already included in the group term Infusion Related Reaction. The most common individual terms within the group term Infusion Related Reaction in decreasing order of frequency are nausea, chills, pyrexia and vomiting. d Includes adverse reactions reported as infusion related reactions. Infusion related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion. Neutropenia includes neutropenia, agranulocytosis, febrile neutropenia, granulocytopenia, and neutrophil count decreased; febrile neutropenia includes febrile neutropenia, neutropenic infection, neutropenic sepsis, and febrile bone marrow aplasia. Thrombocytopenia includes thrombocytopenia and platelet count decreased. Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, sinusitis bacterial, upper respiratory tract infection bacterial, pharyngitis streptococcal, sinusitis fungal, upper respiratory fungal infection, acute sinusitis, chronic sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, rhinovirus infection, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection. A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Hematology Lymphopenia Leukopenia Neutropenia Thrombocytopenia Chemistry ALT/SGPT increased AST/SGOT increased Hypophosphatemia Hypoalbuminemia Hypoproteinemia Hypocalcemia Hyperuricemia Hyponatremia Hyperkalemia Hypernatremia 16 < a Includes lab abnormalities, reported throughout treatment and follow-up, that were new or worsening, or worsening from baseline unknown. Herpesvirus infection includes genital herpes, genital herpes zoster, herpes dermatitis, herpes ophthalmic, herpes simplex, herpes simplex pharyngitis, herpes virus infection, herpes zoster, herpes zoster disseminated, herpes zoster infection neurological, herpes zoster oticus, nasal herpes, ophthalmic herpes simplex, ophthalmic herpes zoster, oral herpes, varicella, varicella zoster virus infection. Pneumonia includes pneumonia bacterial, pneumonia haemophilus, pneumonia pneumococcal, pneumonia fungal, pneumocystis jirovecii infection, pneumocystis jirovecii pneumonia, atypical pneumonia, lung infection, pneumonia, pneumonia aspiration, lung infiltration. Cough includes cough, productive cough, upper-airway cough syndrome. Diarrhea includes diarrhea, defecation urgency, frequent bowel movement, gastroenteritis, gastroenteritis viral. Headache includes cluster headache, headache, sinus headache, tension headache, migraine. Insomnia includes initial insomnia, insomnia, sleep disorder. Pruritus includes pruritus and pruritus generalized. A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). GAZYVA monotherapy investigator-reported adverse reactions 1 The common adverse reactions (incidence 10%) observed at least 2% more with GAZYVA were upper respiratory tract infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%) and herpesvirus infection (13%) GAZYVA monotherapy hematological laboratory abnormalities 1 New-onset Grade 3 or 4 neutropenia was reported in 21% of patients in the GAZYVA arm (Grade 4, 10%) and 17% of patients in the rituximab product arm (Grade 4, 9%) Adverse reactions leading to treatment withdrawal 1 18% in the GAZYVA arm vs 15% in the rituximab arm Safety Profile

8 Incidence of Infusion Reactions by Treatment Cycle GALLIUM Dosing Schedule Infusion-related reactions (IRRs) with GAZYVA may be severe and life threatening, and can occur at any time 1 Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema) Most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills Grades 3 to 4 infusion reactions in the GAZYVA and rituximab arms 3 GAZYVA dosing schedule 1 Day of treatment cycle Dose Rate of infusion Day 1 1,000 mg Rate of infusion: Administer at 50 mg/hr The rate of the infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr Percentage of patients Cycles Cycle Monotherapy 10% 5% 1% 2% <1%<1% <1% 1% <1% 1% 1% 1% <1% <1% <1% Monotherapy Cycle 1 (loading doses) Day 8 Day 15 Cycles 2-6 or 2-8 Day 1 Monotherapy 1,000 mg Rate of infusion: If no infusion reaction or an infusion reaction of Grade 1 occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can 1,000 mg 1,000 mg Every 2 months for up to 2 years 1,000 mg be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr If an infusion reaction of Grade 2 or higher occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr Dosing * IRR data includes 5 additional patients not included in the overall safety analyses. Percentage of patients % 44% 20% 13% Cycles 2-8 GAZYVA based regimen (n=698) * Infusion reactions (all grades) in the GAZYVA and rituximab arms 1,3 Cycle 1 9% 6% Day 2 14% 8% 3 rituximab-based regimen (n=692) * Monotherapy 1% of patients experienced an IRR leading to discontinuation of GAZYVA 9% 8% 7% 8% 9% 6% 6% 7% 3% 3% 2% 2% 4 5 Cycle Monotherapy Patients who achieve a complete or partial response to the initial 6 or 8 cycles of GAZYVA treatment in combination with chemotherapy should continue on GAZYVA 1,000 mg as monotherapy every 2 months for up to 2 years If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible. During GAZYVA and chemotherapy treatment, adjust the dosing schedule accordingly to maintain the time interval between chemotherapy doses. During monotherapy, maintain the original dosing schedule for subsequent doses. Monotherapy should be initiated approximately 2 months after the last induction dose of GAZYVA Administer GAZYVA with one of the following chemotherapy regimens 1 : Six 28-day cycles in combination with bendamustine Six 21-day cycles in combination with CHOP, followed by 2 additional 21-day cycles of GAZYVA alone Eight 21-day cycles in combination with CVP Dosing Per study protocol, GAZYVA was administered on Days 1, 8 and 15 of Cycle 1 and rituximab was administered on Day 1 of Cycle 1. In the rituximab arm, <1% of patients experienced an IRR leading to treatment discontinuation. Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS

9 Recommended Premedication for IRRs Adjusting Infusions in Case of IRRs 1 The following premedications are recommended before beginning the GAZYVA infusion to reduce the risk of IRRs 1 Infusion Reactions Recommendations per Prescribing Information Complete before infusion 60 MINUTES PRIOR Intravenous glucocorticoid a,b 30 MINUTES PRIOR Antihistamine c Cycle 1: Day 1 All patients All patients All Subsequent Infusions Patients with an IRR (Grade 1-2) with the previous infusion Patients with a Grade 3 IRR with the previous infusion OR with a lymphocyte count >25 x 10 9 /L prior to next treatment Grade 4 (life threatening) Grade 3 (severe) Stop infusion immediately and permanently discontinue GAZYVA therapy Interrupt infusion and manage symptoms Upon resolution of symptoms, consider restarting GAZYVA infusion at no more than half the previous rate (the rate being used at the time that the infusion reaction occurred) and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose Permanently discontinue treatment if patients experience a Grade 3 infusion-related symptom at rechallenge Dosing 30 MINUTES PRIOR Acetaminophen d a 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions. b If a glucocorticoid-containing chemotherapy regimen is administered on the same day as GAZYVA, the glucocorticoid can be administered as an oral medication if given at least 1 hour prior to GAZYVA, in which case additional intravenous glucocorticoid as premedication is not required. c Eg, 50 mg diphenhydramine. d 650-1,000 mg. Premedication and close monitoring are recommended for all patients 1 Patients with preexisting cardiac or pulmonary conditions are at a greater risk of experiencing more severe infusion reactions Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 x 10 9 /L), or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis. Premedicate with antihyperuricemics (eg, allopurinol or rasburicase) and ensure adequate hydration prior to start of GAZYVA therapy. Continue prophylaxis prior to each subsequent GAZYVA infusion, as needed Patients with Grade 3 to 4 neutropenia lasting more than one week are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Antiviral and antifungal prophylaxis should be considered (mild to moderate) Reduce infusion rate or interrupt infusion and treat symptoms Upon resolution of symptoms, continue or resume infusion and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS

10 Select GALLIUM Safety Information Select GALLIUM Safety Information Clinical Trial Experience: Adverse Reactions for GAZYVA + Chemotherapy Followed by GAZYVA Monotherapy vs rituximab Product + Chemotherapy Followed by rituximab Monotherapy Infusion Reactions: Overall 72% of patients in the GAZYVA treated arm experienced an infusion reaction (all grades). The incidence of Grade 3 to 4 infusion reactions for these patients was 12%. In Cycle 1, the incidence of infusion reactions (all grades) was 62% in the GAZYVA treated arm with Grade 3 to 4 infusion reactions reported in 10%. The incidence of infusion reactions (all grades) was highest on Day 1 (60%) and decreased on Days 8 and 15 (9% and 6% respectively). During Cycle 2, the incidence of infusion reactions (all grades) in the GAZYVA treated arm was 13% and decreased with subsequent cycles. During GAZYVA monotherapy treatment, infusion reactions (all grades) were observed in 9% of patients. Overall, 1% of patients experienced an infusion reaction leading to discontinuation of GAZYVA Neutropenia: The incidence of neutropenia was higher in the GAZYVA treated arm (53%) compared to the rituximab product treated arm (47%). Cases of prolonged neutropenia (1%) and late onset neutropenia (4%) were also reported in the GAZYVA treated arm. The incidence of neutropenia was higher during treatment with GAZYVA in combination with chemotherapy (45%) compared to the GAZYVA monotherapy treatment phase (20%) Infection: The incidence of infection was 82% in the GAZYVA treated arm and 73% in the rituximab product treated arm, with Grade 3 to 4 events reported in 21% and 17%, respectively. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm. The incidence of Grade 3 to 4 infections in the GAZYVA and rituximab product treated arms was lower in patients receiving GCSF prophylaxis (14%; 16%) compared with patients not receiving GCSF prophylaxis (24%; 18%). The incidence of fatal infections in patients receiving GCSF prophylaxis in the GAZYVA and rituximab product treated arms was 2% and 0%, respectively, and was 2% and <1% in patients not receiving GCSF prophylaxis Clinical Trial Experience: Adverse Reactions for GAZYVA + Chemotherapy Followed by GAZYVA Monotherapy vs rituximab Product + Chemotherapy Followed by rituximab Monotherapy (cont d) Thrombocytopenia: Thrombocytopenia was reported as an adverse reaction in 14% of the GAZYVA treated arm and 8% of the rituximab product treated arm, with the incidence of Grade 3 to 4 events being 7% and 3% respectively. The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 9% in the GAZYVA and 3% in the rituximab product treated arms, with Grade 3 to 4 rates being 5% and 1%, respectively. Both treatment arms had a 12% overall incidence of hemorrhagic events and a <1% incidence of fatal hemorrhagic events Tumor Lysis Syndrome (TLS): The incidence of Grade 3 or 4 TLS was 0.9% in the GAZYVA treated arm Musculoskeletal Disorders: Musculoskeletal disorders were reported in 54% of patients in the GAZYVA treated arm and 49% of patients in the rituximab product treated arm Gastrointestinal Perforation: Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA, mainly in NHL Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA CHOP, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone; CR, complete response; CT, computed tomography; CVP, cyclophosphamide, vincristine sulfate, and prednisone; ECOG, Eastern Cooperative Oncology Group; FLIPI, Follicular Lymphoma International Prognostic Index; PET, positron emission tomography; PR, partial response; PS, Performance Status. Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. References: 1. GAZYVA full Prescribing Information. South San Francisco, CA: Genentech, Inc.; Trotman J, Salles G. Follicular lymphoma. In: Younes A, Coffier B, eds. Lymphoma. Totowa, NJ: Humana Press; 2013; Current Clinical Oncology, vol Data on file. Genentech, Inc

11 Our Commitment to Your GAZYVA Patients Assistance Options for Eligible Patients GAZYVA Access Solutions offers a full range of access and reimbursement support to help you and your patients understand their coverage and get assistance with OOP costs so treatment can begin as soon as possible. The Genentech BioOncology Co-pay Card Genentech offers the Genentech BioOncology Co-pay Card * to help eligible patients with the out-of-pocket costs associated with their GAZYVA prescription. Patients who qualify can receive up to $25,000 in assistance per 12-month period. Please call (855) MYCOPAY/ (855) or see CopayAssistanceNow.com for full terms and conditions, including details on co-pay amounts. We Provide Coverage and Reimbursement Support Services For your practice, we offer assistance navigating the coverage and reimbursement landscape. GAZYVA Access Solutions can help your practice by: Determining your patient s coverage Identifying if a prior authorization (PA) is required and offering resources as you obtain a PA Providing resources for appeals Providing sample billing and coding information We are committed to helping patients access our medicines, regardless of their ability to pay Patient assistance is available for eligible patients with commercial insurance, public insurance or no insurance. GAZYVA Access Solutions offers the following options to help patients with the out-of-pocket (OOP) costs of their Genentech medicines. Each has its own eligibility criteria that must be met for patients to receive assistance. Independent Co-pay Assistance Foundations If eligible publicly or commercially insured patients have difficulty paying for their co-pay, co-insurance, or other out of pocket (OOP) costs, GAZYVA Access Solutions can refer them to an independent co-pay assistance foundation supporting their disease state. Genentech Access to Care Foundation (GATCF) GATCF provides free medicine to eligible patients who are uninsured, rendered uninsured by payer denial or underinsured. To qualify, patients must meet specific criteria. For further information, call GAZYVA Access Solutions at (888) or visit Genentech-Access.com/GAZYVA. REFERRALS TO GAZYVA PATIENT SUPPORT GENENTECH BIOONCOLOGY CO-PAY CARD * COMMERCIALLY INSURED PATIENTS GAZYVA ACCESS SOLUTIONS REFERRALS TO PATIENT ASSISTANCE INDEPENDENT CO-PAY ASSISTANCE FOUNDATIONS GENENTECH ACCESS TO CARE FOUNDATION (GATCF) PUBLICLY INSURED PATIENTS * To be eligible for the Genentech BioOncology Co-pay Card, patients must not have public insurance and must meet other criteria. Genentech does not influence or control the operations or eligibility criteria of any independent co-pay assistance foundation and cannot guarantee co-pay assistance after a referral from GAZYVA Access Solutions. To be eligible for free medicine from GATCF, insured patients must have exhausted all other forms of patient assistance (including the Genentech BioOncology Co-pay Card and support from independent co-pay assistance foundations) and meet specific criteria. Patients must meet eligibility criteria. The completion and submission of coverage- or reimbursement-related documentation are the responsibility of the patient and health care provider. Genentech makes no representation or guarantee concerning coverage or reimbursement for any service or item. Please see Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS. UNINSURED PATIENTS * In order to qualify for the benefits of the Genentech BioOncology Co-pay Card, the patient may be required to pay certain out-of-pocket expenses for each treatment. Patients must also be taking the medication for a Food and Drug Administration (FDA)-approved indication. Patients using Medicare, Medicaid, or any other government-funded program to pay for their medications are not eligible. Patients who start utilizing their government coverage during their enrollment period will no longer be eligible for the program. Once enrolled, this Co-pay Card Program will not honor claims with date of service or medication dispensing that precede program enrollment by more than 120 days. Participating patients, pharmacies, physician offices, and hospitals are responsible for reporting the receipt of all Co-pay Card benefits or reimbursement received to any insurer, health plan, or other third party who pays for or reimburses any part of the prescription filled using the Co-pay Card Program. This card is not health insurance or a benefit plan. The patient or their guardian must be 18 years or older to receive Co-pay Card benefits. This Co-pay Card Program is void if the card is reproduced and where prohibited by law. It is only valid for Genentech products and only valid in the U.S. and Puerto Rico. For Massachusetts residents, the Co-pay Card is not valid for any prescription drug that has an AB-rated generic equivalent as determined by the FDA. The Co-pay Card Program expires within 12 months from enrollment. Genentech, Inc., reserves the right to rescind, revoke, or amend the program without notice at any time. Patient, guardian, pharmacist, prescriber, and any other person using the Co-pay Card agree not to seek reimbursement for all or any part of the benefit received by the recipient through the offer. Additional terms and conditions apply. Genentech does not influence or control the operations or eligibility criteria of any independent co-pay assistance foundation and cannot guarantee co-pay assistance after a referral from Genentech BioOncology Access Solutions. The foundations to which we refer patients are not exhaustive or indicative of Genentech s endorsement or financial support. There may be other foundations to support the patient s disease state Patient Assistance Information

12 NOW APPROVED GAZYVA Is the First and Only Approved Therapy That Demonstrated Superior PFS vs rituximab in Previously Untreated FL 1 With chemotherapy * for stage II bulky, III, and IV patients FL In a disease characterized by recurrent relapses and progressively shorter remissions with each relapse, reducing the risk of disease progression or death is an important goal of first-line FL treatment 2 GALLIUM was a Phase III randomized trial that studied over 1,200 previously untreated adult FL patients to determine whether GAZYVA could improve progression-free survival (PFS) vs rituximab when each was combined with bendamustine, CHOP, or CVP and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded 1,3 The GAZYVA based regimen delivered superior PFS vs the rituximab-based regimen as assessed by independent review committee (IRC), reducing patients risk of disease progression or death by 28% (38-month median observation time; HR=0.72; 95% CI, ; P=0.0118; median PFS was not reached in either arm) 1 * GAZYVA and rituximab were each combined with bendamustine, CHOP, or CVP, and followed by GAZYVA or rituximab monotherapy, respectively, in patients who responded. PFS event was defined as disease progression or death. Indication GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma (FL). Select Important Safety Information BOXED WARNINGS: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA Please see additional Important Safety Information throughout as well as accompanying full Prescribing Information, including BOXED WARNINGS Genentech USA, Inc. All rights reserved. GAZ/092717/0025 Printed in USA. November 2017