Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX CONTENTS METHODS 2 GELF CRITERIA 2 FLIPI RISK FACTORS 2 FULL INCLUSION AND EXCLUSION CRITERIA 2 DOSES OF MONOCLONAL ANTIBODIES (MABS) AND CHEMOTHERAPY 8 PRE-MEDICATIONS AND DOSE MODIFICATIONS 8 ADVERSE EVENT MONITORING 9 RESULTS 9 PATIENT CHARACTERISTICS AND TREATMENT 9 SAFETY 10 SUPPLEMENTARY TABLES 11 SUPPLEMENTARY FIGURES 33 1

3 METHODS GELF CRITERIA To be eligible for inclusion in the study, patients had to require treatment, according to Groupe d étude des lymphomes folliculaires (GELF) criteria. These are as follows: 1. High tumor bulk, i.e. a tumor >7 cm in diameter, three nodes in three distinct areas each measuring >3 cm in diameter, symptomatic spleen enlargement, organ compression, or ascites or pleural effusion. 2. Presence of systemic symptoms. 3. Eastern Cooperative Oncology Group (ECOG) performance status of >1. 4. Serum lactate dehydrogenase or beta2-microglobulin level above normal values. FLIPI RISK FACTORS Five risk factors are used to calculate the Follicular Lymphoma International Prognostic Index (FLIPI) score: 1. Age of >60 years. 2. Stage III or IV disease. 3. At least five nodules or tumors detected, or involvement of at least five lymph node groups. 4. Serum hemoglobin of <12 g/dl 5. Elevated serum lactate dehydrogenase. A patient s FLIPI score is the total number of points, with each factor counting as one point. The three levels of risk based on FLIPI score are low (patients with 1 point), intermediate (2 points) or high (>2 points). FULL INCLUSION AND EXCLUSION CRITERIA Patients had to meet the following criteria for study entry: 2

4 1. Histologically documented, CD20-positive, indolent B-cell non-hodgkin lyphoma (NHL), i.e., follicular lymphoma (FL; grades 1 to 3a) splenic marginal zone lymphoma (MZL), nodal MZL, or extranodal MZL. a. Tissue diagnostic procedures must have been performed during the 12 months prior to randomization. Biopsy material from an excisional or core biopsy must have been submitted for retrospective central confirmation. Tissue samples dated more than 12 months before randomization were accepted only if tissue material was available for retrospective confirmation, if there was no clinical indication for transformation of disease, and if the request for additional biopsy was considered unethical for the patient. Bone marrow alone was not suitable for making a diagnosis of FL. b. Approximately 200 patients with MZL (splenic, nodal, or extranodal) could be randomized, after which point recruitment of patients with MZL was stopped. c. In patients with splenic MZL but with no splenic tissue available for histologic review, the diagnosis could be confirmed by the presence of splenomegaly and typical morphologic and immunophenotypic findings in the blood and bone marrow. Bone marrow had to be submitted for retrospective central confirmation. 2. Stage III or IV disease or stage II bulk disease; bulk disease was defined as a tumor diameter of 7 cm. 3. Patients with FL had to have disease that required treatment, defined as meeting at least one of the following criteria: bulk disease, defined as a nodal or extranodal (except spleen) mass with a greatest diameter of 7 cm; local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass; presence of B symptoms (fever, drenching night sweats, or unintentional weight loss of >10% of normal body weight over a period of 6 months or less); presence of symptomatic extranodal disease (e.g., pleural effusions, peritoneal ascites); cytopenias due to underlying lymphoma (i.e., absolute neutrophil count <1.0 3

5 10 9 /l, hemoglobin <10 g/dl, and/or platelet count < /l); involvement of 3 nodal sites, each with a diameter of 3 cm; symptomatic splenic enlargement. 4. Patients with symptomatic splenic, nodal, or non-gastric extranodal MZL had to have disease that was de novo or had relapsed following local therapy (i.e., surgery or radiotherapy) and required treatment, as assessed by the investigator. 5. Patients with symptomatic gastric extranodal MZL had to have Helicobacter pylori negative disease that was de novo or had relapsed following local therapy (i.e., surgery or radiotherapy) and required treatment, as assessed by the investigator, or H. pylori positive disease that had remained stable, progressed, or relapsed following antibiotic therapy and required treatment, as assessed by the investigator. 6. At least one bi-dimensionally measurable lesion (largest dimension of >2 cm by computerised tomography (CT) scan or magnetic resonance imaging). In patients with splenic MZL, measurable disease meant spleen enlargement on CT scan or extension of the spleen at least 2 cm below the costal margin by physical examination, provided that no explanation other than lymphomatous involvement was likely. For an enlarged liver to constitute the only measurable disease parameter, a liver biopsy showing proof of NHL in the liver was required. 7. Able and willing to provide written informed consent and to comply with the study protocol. 8. Age 18 years. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: hemoglobin 9.0 g/dl; absolute neutrophil count /l; platelet count /l. 11. For men who were not surgically sterile: agreement to use a barrier method of contraception during the treatment phase and for at least 3 months after the last dose of obinutuzumab and rituximab or bendamustine or according to institutional 4

6 guidelines for CHOP (cyclophosphamide [C], doxorubicin, vincristine [V] and prednisone [P]) or CVP, whichever was longer. In addition, male patients had to agree to request that their partners use an additional method of contraception, such as oral contraceptives, intrauterine device, barrier method of contraception, or spermicidal jelly. 12. For women of reproductive potential who are not surgically sterile: agreement to use two adequate methods of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly during the treatment period and for at least 12 months after the last dose of obinutuzumab or rituximab, for at least 3 months after the last dose of bendamustine or according to institutional guidelines for CHOP or CVP, whichever was longer. Patients who met any of the following criteria were excluded from study entry: 1. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy, e.g., patients in whom dosing with rituximab would be contraindicated for safety reasons. 2. Known hypersensitivity to any of the study drugs. 3. Known sensitivity to murine products. 4. History of sensitivity to mannitol. 5. Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma. 6. Grade 3b FL, small lymphocytic lymphoma, or Waldenström s macroglobulinemia. 7. Ann Arbor stage I disease. 8. For patients with FL: prior treatment for NHL by, immunotherapy, or radiotherapy. In this context, low-dose methotrexate (MTX) in rheumatoid arthritis (typically 7.5 to a maximum of 20 mg/week) was not considered for lymphoma. It was recommended that patients stop MTX 2 to 3 weeks prior to starting immuno, because the combination of MTX and immuno increases the risk of immunosuppression and of infection. 5

7 9. For patients with non-fl, prior treatment with or immunotherapy. 10. Regular treatment with corticosteroids during the 4 weeks prior to the start of cycle 1, unless administered for indications other than NHL at a dose equivalent to 30 mg/day of prednisone. Patients receiving corticosteroid treatment with 30 mg/day of prednisone or equivalent had to be documented to be on a stable dose of at least 4 weeks duration prior to randomization. If glucocorticoid treatment was urgently required for medical reasons, e.g., complications imminent if not treated at least with glucocorticoids, or the patient had strong discomfort/pain due to lymphoma, prednisone 100 mg or equivalent could be given for a maximum of 5 consecutive days, but all tumor assessments had to be completed prior to the start of glucocorticoid treatment. Glucocorticoid treatment had to be stopped prior to randomization. In cases when glucocorticoid pre-treatment or pre-phase was done externally prior to considering the patient for study inclusion, glucocorticoids had to be stopped for at least 7 days before screening assessments began. 11. Patients with a history of confirmed progressive multifocal leukoencephalopathy. 12. History of other malignancy, with the exception of: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study; or other cancers not specified above which had been curatively treated by surgery alone and from which the patient was disease-free for 5 years without further treatment. 13. Evidence of significant, uncontrolled concurrent diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm). 14. For patients who were to receive CHOP: left ventricular ejection fraction <50% by multiple-gated acquisition scan or echocardiogram. 6

8 15. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with intravenous (i.v.) antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 4 weeks prior to the start of cycle 1. For patients with suspected latent tuberculosis, the diagnosis had to be confirmed by positive Interferon-gamma release assay. 16. Vaccination with a live vaccine within 28 days prior to randomization. 17. Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis. 18. Any of the following abnormal laboratory values (unless due to underlying lymphoma): a. Creatinine >1.5 x the upper limit of normal (ULN; unless creatinine clearance normal) or calculated creatinine clearance <40 ml/min (using Cockcroft-Gault formula); b. Aspartate aminotransferase or alanine transaminase >2.5 ULN; c. Total bilirubin >1.5 ULN (or >3 ULN for patients with documented Gilbert syndrome); d. International normalized ratio or prothrombin time >1.5 ULN in the absence of therapeutic anticoagulation; e. Partial thromboplastin time (PTT) or activated PTT >1.5 ULN in the absence of a lupus anticoagulant. 19. Positive test results for chronic hepatitis B virus (HBV; defined as positive hepatitis B surface antigen [HBsAg] serology). Patients with occult or prior HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody) could be included if HBV DNA was undetectable, provided that they were willing to undergo monthly DNA testing. Patients who had protective titers of hepatitis B surface antibody after vaccination or prior but cured hepatitis B were eligible. 7

9 20. Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing). Patients positive for HCV antibody were eligible only if polymerase chain reaction assay was negative for HCV RNA. 21. Known history of seropositivity to human immunodeficiency virus (HIV). In countries where mandatory testing by health authorities is required, HIV testing had to be performed. 22. Positive test results for human T-lymphotropic (HTLV)-1 virus. HTLV testing was required in patients from endemic countries (Japan, countries in the Caribbean basin, South America, Central America, sub-saharan Africa, and Melanesia). 23. Pregnant or lactating. 24. Life expectancy <12 months. 25. Participation in another clinical trial with drug intervention within 28 days prior to start of cycle 1 or during the study. DOSES OF MONOCLONAL ANTIBODIES (mabs) AND CHEMOTHERAPY Both mabs (obinutuzumab [G] and rituximab [R]) were administered for six 28-day cycles when combined with bendamustine and for eight 21-day cycles when combined with CHOP and CVP: as patients received CHOP for six 21-day cycles only, patients on R-CHOP or G- CHOP received antibody only in cycles 7 and 8. Doses of were as follows: CHOP cyclophosphamide 750 mg/m², doxorubicin 50 mg/m² and vincristine 1.4 mg/m² (maximum dose 2 mg) by i.v. infusion on day 1 plus prednisone 100 mg orally per day on days 1 to 5 of six 21-day cycles; CVP same doses (for C, V, and P) as in CHOP for eight 21-day cycles; bendamustine 90 mg/m² by i.v. infusion on days 1 and 2 of six 28-day cycles. PRE-MEDICATIONS AND DOSE MODIFICATIONS Acetaminophen and an antihistamine were administered 30 to 60 minutes before mab infusions. Other recommended pre-medications included corticosteroids (at least 1 hour 8

10 before the first mab dose in cycle 1) and anti-emetics. Treatment doses were delayed in the event of grade 3 or 4 hematologic toxicity or grade 2 to4 non-hematologic toxicity for up to 3 weeks (induction) or up to 6 weeks (maintenance); if toxicity did not resolve, the patient was withdrawn from study treatment. Dose reductions were allowed for, but not for mabs. ADVERSE EVENT MONITORING Adverse events (AEs) and serious adverse events (SAEs) were assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. AEs were recorded for the following periods after the last dose of study drug: up to 28 days (any AE), up to 6 months (grade 3 AEs), up to 12 months (unrelated SAEs) and up to 24 months (grade 3 to 4 infections). Drug-related SAEs were collected indefinitely. RESULTS PATIENT CHARACTERISTICS AND TREATMENT Retrospective confirmation of investigator s diagnosis by central laboratories was done for 1258 patients. Of 1099 patients who were diagnosed locally with FL, the diagnosis of FL was confirmed in 1061 (96.5%). Of 159 patients who were diagnosed locally with non-fl disease, that diagnosis was confirmed centrally in 146 (91.8%). 9

11 SAFETY The safety population included fewer patients than the FL intent-to-treat (ITT) population because some patients receiving the wrong antibody or no antibody. Three patients randomized to R-chemo received no antibody and a fourth, who received one dose of G in error, was included in the G-chemo group for safety analysis. Seven patients randomized to G-chemo received no antibody. Two FL ITT patients in the G plus (G-chemo) group received R in error (total doses 1000 mg and 3400 mg, respectively) but remained in the G-chemo group for safety analysis because they were exposed to G. 10

12 SUPPLEMENTARY TABLES 11

13 Table S1: Study Drug Exposure (FL Safety Population); Data are n and % Unless Specified.* Obinutuzumab- (N = 595) Rituximab (N = 597) Induction phase Number of obinutuzumab or rituximab doses received 8.0 (1 10) 6.0 (1 8) median (range) Patients with interruptions to obinutuzumab or rituximab 260/595 (43.7%) 226/597 (37.9%) dose Patients with delays to obinutuzumab or rituximab 92/595 (15.4%) 82/597 (13.7%) doses of >7 days Patients with 90% planned dose intensity of 593 (99.7) 594 (99.5) obinutuzumab or rituximab Duration of exposure to obinutuzumab or rituximab 25.1 ( ) 25.1 ( ) weeks, median (range) Cumulative dose of obinutuzumab or rituximab in mg median (range) Maintenance phase 8000 ( ) ( ) Number of obinutuzumab or rituximab doses received 12 (1 12) 12 (1 12) median (range) Patients with interruptions to obinutuzumab or rituximab 33/540 (6.1%) 35/526 (6.7%) doses Patients with delays to obinutuzumab or rituximab 373/595 (62.7%) 329/597 (55.1%) doses of >7 days Patients with 90% planned dose intensity of 539/540 (99.8) 522/526 (99.2) obinutuzumab or rituximab 12

14 Duration of exposure to obinutuzumab or rituximab 92.3 ( ) 92.1 ( ) weeks, median (range) Cumulative dose of obinutuzumab or rituximab in mg median (range) * FL denotes follicular lymphoma ( ) 7679 ( ) 13

15 Table S2: Number (and %) of Patients Reporting AEs of Any Grade with an Incidence Rate for the Overall Study of at Least 10% (at Preferred Term Level) in Either Treatment Arm, Listed by System Organ Class, Preferred Term, and Treatment Phase (FL Safety Population).* Overall Study Induction Maintenance Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- (N = 595) (N = 597) (N = 595) (N = 597) (N =548) (N = 535) Blood and Lymphatic System Disorders with at least one AE 347 (58.3) 315 (52.8) 309 (51.9) 287 (48.1) 123 (22.4) 97 (18.1) Neutropenia 289 (48.6) 260 (43.6) 247 (41.5) 235 (39.4) 105 (19.2) 70 (13.1) Leukopenia 69 (11.6) 71 (11.9) 59 (9.9) 67 (11.2) 16 (2.9) 18 (3.4) Anemia 53 (8.9) 60 (10.1) 45 (7.6) 53 (8.9) 11 (2.0) 9 (1.7) Thrombocytopenia 68 (11.4) 45 (7.5) 63 (10.6) 43 (7.2) 9 (1.6) 2 (0.4) Gastrointestinal Disorders 14

16 with at least one AE 472 (79.3) 449 (75.2) 446 (75.0) 423 (70.9) 177 (32.3) 145 (27.1) Nausea 279 (46.9) 278 (46.6) 272 (45.7) 266 (44.6) 23 (4.2) 35 (6.5) Constipation 210 (35.3) 188 (31.5) 197 (33.1) 176 (29.5) 21 (3.8) 16 (3.0) Diarrhea 160 (26.9) 131 (21.9) 117 (19.7) 98 (16.4) 54 (9.9) 46 (8.6) Vomiting 139 (23.4) 122 (20.4) 120 (20.2) 103 (17.3) 25 (4.6) 22 (4.1) Abdominal pain 61 (10.3) 64 (10.7) 51 (8.6) 48 (8.0) 16 (2.9) 20 (3.7) General Disorders and Administration Site Conditions with at least one AE 443 (74.5) 411 (68.8) 408 (68.6) 373 (62.5) 123 (22.4) 144 (26.9) Fatigue 214 (36.0) 218 (36.5) 195 (32.8) 186 (31.2) 40 (7.3) 59 (11.0) Pyrexia 164 (27.6) 127 (21.3) 143 (24.0) 111 (18.6) 29 (5.3) 25 (4.7) Chills 99 (16.6) 56 (9.4) 95 (16.0) 52 (8.7) 5 (0.9) 5 (0.9) Infections and Infestations with at least one AE 460 (77.3) 418 (70.0) 284 (47.7) 276 (46.2) 353 (64.4) 290 (54.2) 15

17 Upper respiratory tract infection 112 (18.8) 107 (17.9) 52 (8.7) 51 (8.5) 64 (11.7) 59 (11.0) Nasopharyngitis 102 (17.1) 109 (18.3) 43 (7.2) 49 (8.2) 75 (13.7) 73 (13.6) Urinary tract infection 64 (10.8) 54 (9.0) 29 (4.9) 29 (4.9) 32 (5.8) 31 (5.8) Injury, Poisoning, and Procedural Complications with at least one AE 380 (63.9) 329 (55.1) 361 (60.7) 295 (49.4) 78 (14.2) 79 (14.8) Infusion-related reaction 351 (59.0) 292 (48.9) 345 (58.0) 279 (46.7) 39 (7.1) 36 (6.7) Metabolism and Nutrition Disorders with at least one AE 162 (27.2) 148 (24.8) 124 (20.8) 119 (19.9) 56 (10.2) 47 (8.8) Decreased appetite 69 (11.6) 74 (12.4) 63 (10.6) 69 (11.6) 9 (1.6) 7 (1.3) Musculoskeletal and Connective Tissue Disorders 16

18 with at least one AE 294 (49.4) 266 (44.6) 192 (32.3) 191 (32.0) 176 (32.1) 139 (26.0) Back pain 79 (13.3) 96 (16.1) 49 (8.2) 64 (10.7) 34 (6.2) 35 (6.5) Arthralgia 88 (14.8) 79 (13.2) 44 (7.4) 45 (7.5) 44 (8.0) 34 (6.4) Nervous System Disorders with at least one AE 342 (57.5) 309 (51.8) 303 (50.9) 263 (44.1) 96 (17.5) 107 (20.0) Headache 122 (20.5) 101 (16.9) 106 (17.8) 87 (14.6) 27 (4.9) 27 (5.0) Psychiatric Disorders with at least one AE 137 (23.0) 140 (23.5) 107 (18.0) 108 (18.1) 41 (7.5) 47 (8.8) Insomnia 86 (14.5) 71 (11.9) 71 (11.9) 60 (10.1) 16 (2.9) 17 (3.2) Respiratory, Thoracic, and Mediastinal Disorders 17

19 with at least one AE 324 (54.5) 311 (52.1) 245 (41.2) 234 (39.2) 160 (29.2) 142 (26.5) Cough 152 (25.5) 144 (24.1) 83 (13.9) 71 (11.9) 86 (15.7) 88 (16.4) Dyspnea 87 (14.6) 73 (12.2) 77 (12.9) 62 (10.4) 10 (1.8) 13 (2.4) Oropharyngeal pain 65 (10.9) 60 (10.1) 54 (9.1) 49 (8.2) 15 (2.7) 15 (2.8) Skin and Subcutaneous Tissue Disorders with at least one AE 324 (54.5) 307 (51.4) 282 (47.4) 274 (45.9) 105 (19.2) 89 (16.6) Rash 93 (15.6) 108 (18.1) 79 (13.3) 88 (14.7) 17 (3.1) 22 (4.1) Pruritus 75 (12.6) 83 (13.9) 63 (10.6) 66 (11.1) 15 (2.7) 19 (3.6) Alopecia 80 (13.4) 68 (11.4) 77 (12.9) 67 (11.2) 4 (0.7) 1 (0.2) * AE denotes adverse events, and FL follicular lymphoma. Includes AEs occurring during the induction, maintenance, and post-treatment follow-up phases (AEs starting in the pre-treatment phase are excluded); patients who had a given AE in more than one study phase are only counted once in the overall study column. 18

20 Table S3. Number (and %) of Patients Reporting AEs of Grade 3 to 5 with an Incidence Rate for the Overall Study of at least 2% (at Preferred Term Level) in Either Treatment Arm, Listed by System Organ Class, Preferred Term and Treatment Phase (FL Safety Population).* Overall Study Induction Maintenance Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- (N = 595) (N = 597) (N = 595) (N = 597) (N = 548) (N = 535) Blood and Lymphatic System Disorders with at least one AE 303 (50.9) 262 (43.9) 264 (44.4) 237 (39.7) 100 (18.2) 64 (12.0) Neutropenia 261 (43.9) 226 (37.9) 221 (37.1) 203 (34.0) 90 (16.4) 57 (10.7) Leukopenia 51 (8.6) 50 (8.4) 46 (7.7) 48 (8.0) 5 (0.9) 3 (0.6) Febrile neutropenia 41 (6.9) 29 (4.9) 29 (4.9) 22 (3.7) 12 (2.2) 6 (1.1) Thrombocytopenia 36 (6.1) 16 (2.7) 35 (5.9) 16 (2.7) 3 (0.5) 0 Anemia 24 (4.0) 13 (2.2) 20 (3.4) 12 (2.0) 6 (1.1) 1 (0.2) Infections and Infestations 19

21 with at least one AE 118 (19.8) 93 (15.6) 44 (7.4) 43 (7.2) 64 (11.7) 51 (9.5) Pneumonia 29 (4.9) 26 (4.4) 7 (1.2) 8 (1.3) 14 (2.6) 16 (3.0) Injury, Poisoning, and Procedural Complications with at least one AE 52 (8.7) 31 (5.2) 41 (6.9) 24 (4.0) 11 (2.0) 8 (1.5) Infusion-related reaction 40 (6.7) 22 (3.7) 39 (6.6) 21 (3.5) 3 (0.5) 1 (0.2) Respiratory, Thoracic, and Mediastinal Disorders with at least one AE 51 (8.6) 27 (4.5) 37 (6.2) 22 (3.7) 14 (2.6) 5 (0.9) Dyspnea 17 (2.9) 9 (1.5) 14 (2.4) 7 (1.2) 3 (0.5) 2 (0.4) Vascular Disorders with at least one AE 29 (4.9) 19 (3.2) 24 (4.0) 16 (2.7) 5 (0.9) 4 (0.7) Hypertension 14 (2.4) 10 (1.7) 12 (2.0) 8 (1.3) 3 (0.5) 2 (0.4) * AE denotes adverse event, and FL follicular lymphoma. Includes AEs occurring during the induction, maintenance, and post-treatment follow-up phases (AEs starting in the pre-treatment phase are excluded); patients who had a given AE in more than one study phase are only counted once in the overall study column. 20

22 Table S4. Number (and %) of Patients Reporting SAEs with an Incidence Rate for the Overall Study of at least 0.5% (at Preferred Term Level) in Either Treatment Arm, Listed by System Organ Class, Preferred Term, and Treatment Phase (FL Safety Populatio n).* Overall Study Induction Maintenance Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- (N = 595) (N = 597) (N = 595) (N = 597) (N = 548) (N = 535) Blood and Lymphatic System Disorders with at least one SAE 56 (9.4) 47 (7.9) 42 (7.1) 34 (5.7) 15 (2.7) 14 (2.6) Febrile neutropenia 29 (4.9) 19 (3.2) 18 (3.0) 13 (2.2) 10 (1.8) 6 (1.1) Neutropenia 22 (3.7) 25 (4.2) 17 (2.9) 19 (3.2) 4 (0.7) 8 (1.5) Leukopenia 3 (0.5) 5 (0.8) 3 (0.5) 4 (0.7) 0 0 Thrombocytopenia 4 (0.7) 1 (0.2) 4 (0.7) 1 (0.2) 1 (0.2) 0 Anemia 4 (0.7) 0 4 (0.7) Cardiac Disorders 21

23 with at least one SAE 26 (4.4) 12 (2.0) 15 (2.5) 4 (0.7) 9 (1.6) 7 (1.3) Atrial fibrillation 4 (0.7) 1 (0.2) 2 (0.3) 1 (0.2) 3 (0.5) 0 Sinus bradycardia 5 (0.8) 0 5 (0.8) Acute infarction myocardial 4 (0.7) 0 1 (0.2) 0 1 (0.2) 0 Cardiac failure 1 (0.2) 3 (0.5) 0 2 (0.3) 1 (0.2) 1 (0.2) Gastrointestinal Disorders with at least one SAE 43 (7.2) 28 (4.7) 29 (4.9) 21 (3.5) 14 (2.6) 6 (1.1) Diarrhea 8 (1.3) 6 (1.0) 5 (0.8) 4 (0.7) 2 (0.4) 1 (0.2) Abdominal pain 8 (1.3) 5 (0.8) 7 (1.2) 4 (0.7) 1 (0.2) 1 (0.2) Vomiting 3 (0.5) 7 (1.2) 3 (0.5) 6 (1.0) 0 1 (0.2) Nausea 4 (0.7) 2 (0.3) 4 (0.7) 2 (0.3) 0 0 Pancreatitis 4 (0.7) 1 (0.2) 2 (0.3) 0 3 (0.5) 1 (0.2) Constipation 3 (0.5) 1 (0.2) 3 (0.5) 1 (0.2) 0 0 Intestinal obstruction 3 (0.5) 0 1 (0.2) 0 2 (0.4) 0 22

24 General Disorders and Administration Site Conditions with at least one SAE 30 (5.0) 34 (5.7) 20 (3.4) 28 (4.7) 11 (2.0) 4 (0.7) Pyrexia 18 (3.0) 17 (2.8) 15 (2.5) 16 (2.7) 6 (1.1) 1 (0.2) Chills 3 (0.5) 3 (0.5) 3 (0.5) 2 (0.3) 0 1 (0.2) Chest pain 2 (0.3) 3 (0.5) 0 3 (0.5) 1 (0.2) 0 Multi-organ failure 0 3 (0.5) 0 2 (0.3) 0 1 (0.2) Hepatobiliary Disorders with at least one SAE 11 (1.8) 9 (1.5) 4 (0.7) 3 (1.5) 7 (1.3) 5 (0.9) Cholecystitis 4 (0.7) 5 (0.8) 1 (0.2) 1 (0.2) 3 (0.5) 3 (0.6) Infections and Infestations with at least one SAE 107 (18.0) 86 (14.4) 44 (7.4) 38 (6.4) 54 (9.9) 45 (8.4) Pneumonia 29 (4.9) 25 (4.2) 9 (1.5) 7 (1.2) 13 (2.4) 16 (3.0) Herpes zoster 6 (1.0) 8 (1.3) 1 (0.2) 4 (0.7) 3 (0.5) 1 (0.2) Infection 5 (0.8) 7 (1.2) 3 (0.5) 6 (1.0) 3 (0.5) 1 (0.2) 23

25 Urinary tract infection 7 (1.2) 5 (0.8) 2 (0.3) 3 (0.5) 2 (0.4) 2 (0.4) Lower respiratory tract infection 8 (1.3) 3 (0.5) 3 (0.5) 0 3 (0.5) 2 (0.4) Lung infection 5 (0.8) 6 (1.0) 3 (0.5) 5 (0.8) 1 (0.2) 1 (0.2) Sepsis 8 (1.3) 2 (0.3) 5 (0.8) 2 (0.3) 3 (0.5) 0 Bronchitis 6 (1.0) 3 (0.5) 2 (0.3) 1 (0.2) 4 (0.7) 1 (0.2) Gastroenteritis 7 (1.2) 1 (0.2) 3 (0.5) 0 4 (0.7) 1 (0.2) Upper respiratory tract infection 5 (0.8) 3 (0.5) 0 3 (0.5) 4 (0.7) 0 Respiratory tract infection 3 (0.5) 2 (0.3) 0 1 (0.2) 2 (0.4) 1 (0.2) Appendicitis 1 (0.2) 4 (0.7) (0.2) 3 (0.6) Urosepsis 3 (0.5) 2 (0.3) 1 (0.2) 1 (0.2) 2 (0.4) 1 (0.2) Device related infection 1 (0.2) 3 (0.5) 1 (0.2) (0.4) Atypical pneumonia 0 3 (0.5) 0 2 (0.3) 0 1 (0.2) Neutropenic sepsis 0 3 (0.5) 0 1 (0.2) 0 2 (0.4) Viral infection 0 3 (0.5) 0 2 (0.3) 0 0 Injury, Poisoning, and Procedural Complications 24

26 with at least one SAE 41 (6.9) 21 (3.5) 32 (5.4) 16 (2.7) 7 (1.3) 5 (0.9) Infusion-related reaction 27 (4.5) 11 (1.8) 26 (4.4) 11 (1.8) 2 (0.4) 0 Fall 3 (0.5) 1 (0.2) 2 (0.3) (0.2) Metabolism and Nutrition Disorders with at least one SAE 16 (2.7) 6 (1.0) 14 (2.4) 4 (0.7) 2 (0.4) 0 Dehydration 3 (0.5) 2 (0.3) 3 (0.5) 1 (0.2) 0 0 Hyponatremia 4 (0.7) 1 (0.2) 3 (0.5) 1 (0.2) 1 (0.2) 0 Tumor lysis syndrome 3 (0.5) 1 (0.2) 3 (0.5) 1 (0.2) 0 0 Musculoskeletal and Connective Tissue Disorders with at least one SAE 11 (1.8) 12 (2.0) 1 (0.2) 4 (0.7) 9 (1.6) 7 (1.3) Back pain 1 (0.2) 3 (0.5) 0 2 (0.3) 0 1 (0.2) 25

27 Neoplasms Benign, Malignant and Unspecified (incl. Cysts and Polyps) with at least one SAE 38 (6.4) 21 (3.5) 4 (0.7) 3 (0.5) 22 (4.0) 16 (3.0) Basal cell carcinoma 4 (0.7) 2 (0.3) 0 1 (0.2) 2 (0.4) 1 (0.2) Prostate cancer 3 (0.5) 3 (0.5) (0.2) 2 (0.4) Breast cancer 4 (0.7) (0.5) 0 Squamous cell carcinoma 3 (0.5) 1 (0.2) (0.4) 1 (0.2) Nervous System Disorders with at least one SAE 16 (2.7) 21 (3.5) 6 (1.0) 11 (1.8) 9 (1.6) 7 (1.3) Transient ischemic attack 4 (0.7) 0 1 (0.2) 0 3 (0.5) 0 Presyncope 0 3 (0.5) 0 2 (0.3) 0 1 (0.2) Respiratory, Thoracic, and Mediastinal Disorders with at least one SAE 33 (5.5) 30 (5.0) 21 (3.5) 21 (3.5) 13 (2.4) 7 (1.3) 26

28 Dyspnea 6 (1.0) 6 (1.0) 4 (0.7) 5 (0.8) 2 (0.4) 1 (0.2) Pulmonary embolism 6 (1.0) 2 (0.3) 5 (0.8) 2 (0.3) 2 (0.4) 0 Pleural effusion 3 (0.5) 4 (0.7) 3 (0.5) 4 (0.7) 0 0 Interstitial lung disease 2 (0.3) 4 (0.7) 2 (0.3) 4 (0.7) 0 0 Chronic obstructive pulmonary disease 0 3 (0.5) 0 2 (0.3) 0 0 Vascular Disorders with at least one SAE 12 (2.0) 7 (1.2) 10 (1.7) 7 (1.2) 2 (0.4) 0 Hypotension 6 (1.0) 0 6 (1.0) Embolism 0 3 (0.5) 0 3 (0.5) 0 0 * FL denotes follicular lymphoma, and SAE serious adverse event. Includes SAEs occurring during the induction, maintenance, and post-treatment follow-up phases (SAEs starting in the pre-treatment phase are excluded); patients who had a given SAE in more than one study phase are only counted once in the overall study column. 27

29 Table S5: Number (and %) of Patients Reporting Treatment-Emergent AEs in the Pre-defined Category Secondary Neoplasms (FL Safety Population).* Category Non-melanoma skin cancer Obinutuzumab (N = 595) All AEs Grade 3 to 5 AEs SAEs Rituximab (N = 597) Obinutuzumab (N = 595) Rituximab (N = 597) Obinutuzumab (N = 595) Rituximab (N = 597) Basal cell carcinoma 11 (1.8) 6 (1.0) 2 (0.3) 1 (0.2) 4 (0.7) 1 (0.2) Squamous cell carcinoma 5 (0.8) 5 (0.8) 3 (0.5) 1 (0.2) 3 (0.5) 1 (0.2) Bowen's disease 0 3 (0.5) Squamous cell carcinoma 2 (0.3) 0 2 (0.3) 0 2 (0.3) 0 of skin Hematologic cancer Acute myeloid leukaemia 2 (0.3) 0 2 (0.3) 0 2 (0.3) 0 Hodgkin's disease 2 (0.3) 0 2 (0.3) 0 2 (0.3) 0 Acute lymphocytic 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 leukaemia 28

30 Hodgkin's disease nodular 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 sclerosis Other Prostate cancer 4 (0.7) 3 (0.5) 2 (0.3) 3 (0.5) 3 (0.5) 3 (0.5) Breast cancer 4 (0.7) 0 4 (0.7) 0 4 (0.7) 0 Colon cancer 0 2 (0.3) 0 1 (0.2) 0 2 (0.3) Invasive ductal breast 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) carcinoma Malignant melanoma 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Rectal adenocarcinoma 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) Adenocarcinoma 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Adenocarcinoma of colon 1 (0.2) (0.2) 0 Colorectal cancer 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Follicular thyroid cancer 1 (0.2) 0 1 (0.2)

31 Gastric cancer 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Hepatic neoplasm 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 Intraductal proliferative 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) breast lesion Intraocular melanoma 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Lung adenocarcinoma 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Nasal neoplasm 1 (0.2) Neoplasm 0 1 (0.2) Neoplasm skin 0 1 (0.2) Neuroendocrine 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) carcinoma of the skin Non-small cell lung cancer 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 Non-small cell lung cancer 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 stage IV 30

32 Papillary thyroid cancer 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 Renal cancer 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 Renal cell carcinoma 0 1 (0.2) 0 1 (0.2) 0 1 (0.2) Squamous cell carcinoma 1 (0.2) of lung Thyroid cancer 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 Transitional cell carcinoma 1 (0.2) 0 1 (0.2) 0 1 (0.2) 0 * AE denotes adverse event, FL follicular lymphoma, MedDRA Medical Dictionary for Regulatory Activities, and SAE serious adverse events. Standardized MedDRA query for malignant or unspecified tumors starting >6 months after start of study treatment 31

33 Table S6. Reduction in Immunoglobulin (Ig) Levels (FL Safety Population).* IgA (g/l) IgG (g/l) IgM (g/l) Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- Obinutuzumab- Rituximab- Ig status at last antibody administration no. (%) (N = 595) (N = 597) (N = 595) (N = 597) (N = 595) (N = 597) Depleted 38 (6.4) 57 (9.5) 56 (9.4) 69 (11.6) 177 (29.7) 173 (29.0) Not depleted 420 (70.6) 388 (65.0) 403 (67.7) 375 (62.8) 281 (47.2) 271 (45.4) Not assessed 137 (23.0) 152 (25.5) 136 (22.9) 153 (25.6) 137 (23.0) 153 (25.6) * FL denotes follicular lymphoma. Serum Ig concentrations below 0.5 g/l (IgA), 5.0 g/l (IgG), or 0.3 g/l (IgM). 32

34 SUPPLEMENTARY FIGURES 33

35 Figure S1. Disposition, FL Patients.* * AE denotes adverse events, FL follicular lymphoma, G-chemo obinutuzumab plus, ITT intent-to-treat, MZL marginal zone lymphoma, and R-chemo rituximab plus. 34

36 Figure S2. Kaplan-Meier estimates of (A) Independent Review Committee-assessed PFS, (B) TTNT, and (C) EFS in follicular lymphoma patients.* * CI denotes confidence interval, EFS event-free survival, G-chemo obinutuzumab plus, HR hazard ratio, PFS progression-free survival, R-chemo rituximab plus, and TTNT time to new anti-lymphoma treatment. 35

37 Figure S3. Unstratified HRs for Investigator-assessed PFS by Patient Subgroups in FL ITT Population: (A) Randomization Stratification Factors; (B) Baseline Characteristics.* * ADL denotes activities of daily living, CHOP cyclophosphamide, doxorubicin, vincristine and prednisone, CI confidence interval, CVP cyclophosphamide, vincristine and prednisone, ECOG Eastern Cooperative Oncology Group, FL follicular lymphoma, G-chemo obinutuzumab plus, HR hazard ratio, IADL instrumental activities of daily living, IPI International Prognostic Index, ITT intent-to-treat, KM Kaplan-Meier, PFS progression-free survival, and R-chemo rituximab plus. 36

38 Figure S4. Exploratory Subgroup Analysis of the Effect of Weight on Investigatorassessed PFS in FL ITT Population (Unstratified HRs; Median Body Weight for all Patients = kg; 1st and 3rd Quartiles = and 86 kg).* * CI denotes confidence interval, FL follicular lymphoma, G-chemo obinutuzumab plus, HR hazard ratio, ITT intent-to-treat, KM Kaplan-Meier, PFS progression-free survival, and R-chemo rituximab plus. 37

39 Figure S5. Exploratory Subgroup Analysis of the Effect of BSA on Investigatorassessed PFS in FL ITT Population (Unstratified HRs; Median BSA for all Patients = 1.84 M 2 ; 1st and 3rd Quartiles = 1.67 and 2.00 M 2 ).* * BSA denotes body surface area, CI confidence interval, FL follicular lymphoma, G-chemo obinutuzumab plus, HR hazard ratio, ITT intent-to-treat, KM Kaplan-Meier, PFS progression-free survival, and R-chemo rituximab plus. 38

40 Figure S6. Exploratory Subgroup Analysis of the Effect of Age on Investigatorassessed PFS in FL ITT Population (Unstratified HRs).* * CI denotes confidence interval, FL follicular lymphoma, G-chemo obinutuzumab plus, HR hazard ratio, ITT intent-to-treat, KM Kaplan-Meier, PFS progression-free survival, and R-chemo rituximab plus. 39

41 Figure S7. Incidence, Nature and Timing of Non-relapse Fatal AEs by Chemotherapy Agent and Treatment Arm in FL ITT Population.* * AE denotes adverse events, B bendamustine, CHOP cyclophosphamide, doxorubicin, vincristine and prednisone, CVP cyclophosphamide, vincristine and prednisone, FL follicular lymphoma, G obinutuzumab, ITT intent-to-treat, R rituximab, and SOC System Organ Class. In the right-hand panel, triangles depict fatal AEs that occurred after the patient had started new anti-lymphoma treatment. 40