1.1 Chronic Lymphocytic Leukemia (CLL)

GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia.

1.2 Follicular Lymphoma (FL)

GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen.

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.

1.3 Lupus Nephritis (LN)

GAZYVA is indicated for the treatment of adult patients with active lupus nephritis who are receiving standard therapy.

2.1 Important Dosing Information

• Premedicate before each infusion [see Dosage and Administration (2.4)].
• Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)].
• Administer only as an intravenous infusion through a dedicated line [see Dosage and Administration (2.6)].
• Do not administer as an intravenous push or bolus.
• Monitor blood counts at regular intervals.
• GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions (5.3)].

2.2 Recommended Dosage for Chronic Lymphocytic Leukemia

Each dose of GAZYVA is 1,000 mg administered intravenously with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg) according to Table 1.

If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible and adjust dosing schedule to maintain the time interval between doses. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the Day 2 Cycle 1 dose.

2.3 Recommended Dosage for Follicular Lymphoma

Each dose of GAZYVA is 1,000 mg administered intravenously according to Table 2.

For patients with relapsed or refractory FL, administer GAZYVA in combination with bendamustine in six 28-day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

For patients with previously untreated FL, administer GAZYVA with one of the following chemotherapy regimens:

• 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

Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

GAZYVA should be administered at the standard infusion rate in Cycle 1 (see Table 2). In patients with FL who do not experience a Grade 3 or higher IRR during Cycle 1, GAZYVA may be administered as a shorter, approximately 90-minute infusion from Cycle 2 onwards (see Table 3) with continued premedication.

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 cycles. During monotherapy, maintain the original dosing schedule for subsequent doses. Initiate monotherapy approximately two months after the last dose of GAZYVA administered during the induction phase.

2.4 Recommended Dosage for Active Lupus Nephritis

Each recommended dose of GAZYVA is 1,000 mg administered intravenously according to Table 4.

Patients who do not experience Grade ≥ 3 infusion related reactions during the previous infusion may receive GAZYVA over approximately 90 minutes from Dose 2 onwards (see Table 5), with continued premedication.

If a planned dose of GAZYVA is missed, it should be administered as soon as possible – do not wait until the next planned dose. The schedule of administration should be adjusted to maintain the appropriate interval between doses.

2.5 Recommended Premedication and Prophylactic Medications

2.6 Dosage Modifications for Adverse Reactions

2.7 Preparation and Administration

5.1 Hepatitis B Virus Reactivation

GAZYVA can cause 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 such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also 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 (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

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, i.e., 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 healthcare providers 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. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

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 healthcare providers with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal Leukoencephalopathy

John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, occurred in patients treated with GAZYVA for CLL and NHL. 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.

5.3 Infusion-Related Reactions

GAZYVA can cause severe and life-threatening infusion-related reactions (IRRs). Sixty-five percent of patients with CLL experienced a reaction to the first 1,000 mg of GAZYVA infused. Thirty-seven percent of patients with relapsed or refractory NHL and 60% of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. In patients with CLL and NHL , IRRs have occurred within 24 hours of receiving GAZYVA. IRRs can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). The most frequently reported IRR symptoms in patients with CLL and NHL include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

In patients with LN, IRRs occurred predominantly during infusion of the first 1,000 mg. IRRs were generally mild to moderate and could be managed by the slowing or temporarily halting the infusion [see Dosage and Administration (2.6)]. Severe and life-threatening IRRs requiring symptomatic treatment were also reported. The most common IRR signs or symptoms reported in the REGENCY study included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia [see Adverse Reactions (6.2)].

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid [see Dosage and Administration (2.4)]. Closely monitor patients during the entire infusion. Reduce infusion rate, interrupt infusion or permanently discontinue GAZYVA for IRRs based on severity [see Dosage and Administration (2.5)]. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for IRRs as needed.

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 IRR to GAZYVA. Consider withholding antihypertensive treatments for 12 hours prior to, 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 as is suggested here.

5.4 Hypersensitivity Reactions Including Serum Sickness

Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and tachycardia. Late-onset 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 IRRs. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs after previous exposure.

If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. GAZYVA is contraindicated in patients with known hypersensitivity reactions to GAZYVA, including serum sickness with prior GAZYVA use [see Contraindications (4)].

5.5 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), including fatal cases, has been reported in patients with CLL and NHL receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (> 25 × 109/L) or renal impairment are at greater risk for TLS.

In patients with CLL and NHL at risk for TLS, administer appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA [see Dosage and Administration (2.4)]. 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. TLS is not identified as a risk in LN.

5.6 Serious, Including Fatal, 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 as in the GALLIUM study, 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 [see Adverse Reactions (6.1)].

5.7 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 dose delays for Grade 3 or 4 neutropenia. 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). 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.

5.8 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 and CLL treated with GAZYVA in combination with chemotherapy, including during Cycle 1.

Monitor patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle and if clinically indicated, evaluate laboratory coagulation parameters [see Warnings and Precautions (5.9)]. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider 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 that may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.9 Disseminated Intravascular Coagulation (DIC)

Fatal and severe DIC has been reported in patients receiving GAZYVA for treatment of CLL and NHL. The majority of DIC cases have involved changes in platelets and laboratory coagulation parameters following the first infusion, with spontaneous resolution usually occurring by Day 8. In some cases, DIC was associated with IRRs, TLS, or both [see Adverse Reactions (6.1)].

In patients with suspected DIC, evaluate potential causes, and monitor coagulation parameters, platelet counts, and for signs and symptoms of bleeding or thrombosis. Manage according to standard guidelines for DIC. Supportive care, including transfusion of blood products and other medical management, may be necessary.

5.10 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 with GAZYVA and until B-cell recovery.

5.11 Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animals, GAZYVA can cause B-cell depletion in infants exposed to obinutuzumab in-utero. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception while taking GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of GAZYVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Immune/Autoimmune Events: Serum sickness

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of GAZYVA in pediatric patients have not been established.

8.5 Geriatric Use

12.1 Mechanism of Action

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.

As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

12.2 Pharmacodynamics

In patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B cell counts < 0.07 × 109/L). Initial CD19 B cell recovery was observed in some patients approximately 9 months after the last GAZYVA dose. At 18 months of follow-up, some patients remain B cell depleted.

Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B-cells in solid organs or in malignant deposits. B cell depletion has not been shown to be directly correlated to clinical response.

In patients with LN (REGENCY study), total peripheral CD19+ B cell levels below the defined threshold of 10 cells/µl were achieved in 99% of patients treated with GAZYVA by Week 4 after treatment initiation and remained below this threshold in 95% of patients at Week 76.

Reductions in circulating naive B, memory B, and plasmablasts/plasma cells were observed by Week 4 and remained low through Week 76 after treatment initiation.

Treatment with GAZYVA led to improvements in complement (C3 and C4) and anti-double-stranded DNA antibodies (anti-dsDNA) by Week 4 and Week 12, respectively. These changes were sustained through Week 76.

In patients with low C3 at baseline, normalization of C3 levels occurred in 49% (by Week 12) and in 62% (by Week 76) of patients receiving GAZYVA compared to 33% and 29%, respectively, in the placebo group. In patients with low C4 at baseline, normalization of C4 levels occurred in 75% (by Week 12) and in 88% (by Week 76) of patients receiving GAZYVA compared to 55% and 55%, respectively, in the placebo group. Among patients with positive anti-dsDNA at baseline, 32% and 56% of patients treated with GAZYVA seroconverted by Week 4 and Week 76, respectively, compared with 16% and 16% of patients receiving placebo.

The clinical relevance of the above mentioned pharmacodynamic biomarkers has not been established.

12.3 Pharmacokinetics

The pharmacokinetic parameters of obinutuzumab after 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1,000 mg on day 8 and 15 of Cycle 1, and 1,000 mg on day 1 of Cycles 2-6 for CLL; after 1,000 mg on day 1, 8 and 15 of Cycle 1, 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8, and then 1,000 mg every 2 months for up to 2 years for NHL; 1,000 mg on day 1, week 2, 24, 26 and every 6 months for up to 76 Weeks for LN are provided in Table 14. The dosing regimen is within the linear pharmacokinetic behavior of obinutuzumab.

12.6 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of anti-drug antibody (ADA) (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies or to other products may be misleading.

Seven percent (18/271) of patients with CLL tested positive for anti-GAZYVA antibodies at one or more time points in CLL11. No patients developed anti-GAZYVA antibodies during or following GAZYVA treatment in GADOLIN, while 1 patient (1/564, 0.2%) developed anti-GAZYVA antibodies in GALLIUM. Neutralizing activity of anti-GAZYVA antibodies was not assessed.

In GAZYVA-treated patients in the LN studies, a total of 12 out of 200 (6%) had at least one ADA-positive sample recorded at any time during the studies. Six (3%) subjects had ADA-positive samples recorded at baseline in which two patients remained ADA-positive throughout the studies, one patient had a single post-baseline sample that was ADA-positive, and three patients had post-baseline samples that were all ADA-negative. Six (3%) patients with ADA-negative samples at baseline had a positive ADA titer post-baseline (treatment-induced ADA). None of the 12 patients with positive ADA titers at any time during the treatment period experienced an IRR or hypersensitivity reaction during the studies. Neutralizing activity of anti-GAZYVA antibodies was not assessed.

Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety and/or effectiveness of GAZYVA is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with obinutuzumab.

No specific studies have been conducted to evaluate potential effects on fertility; however, no adverse effects on male or female reproductive organs were observed in the 26-week repeat-dose toxicity study in cynomolgus monkeys.

14.1 Chronic Lymphocytic Leukemia

The efficacy of GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (CLL11; NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CLcr) < 70 mL/min. Patients with CLcr < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

The majority of patients received 1,000 mg of GAZYVA on days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.2)], which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

In CLL11, the median age was 73 years, 62% were male, and 95% were White. Sixty-five percent had a CLcr < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CLcr was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab product treated arm and 67% in the chlorambucil alone arm.

In the Stage 1 analysis of CLL11, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

In the Stage 2 analysis of CLL11, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab product arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value < 0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 104 leukocytes in the sample (i.e., an MRD value of < 10-4 was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi; 94 patients in the GAZYVA arm and 34 patients in the rituximab product arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab product arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm, and 4 patients (12%) in the rituximab product arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

Efficacy results are shown in Table 16 and Figures 1 and 2.

Figure 1 Kaplan-Meier Curve of Overall Survival in Patients with CLL in CLL11 (Stage 1)

Figure 2 Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in CLL11 (Stage 2)

14.2 Follicular Lymphoma

GADOLIN

The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m2/day when given in combination with GAZYVA or 120 mg/m2/day when given alone.

The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

Efficacy results are summarized in Table 17. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

Table 17 Primary Analysis Efficacy Results from GADOLIN*, †

Endpoint	GADOLIN
	GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 155	Bendamustine n = 166
* Based on FL population. † As defined by independent review. ‡ Best response of PR or CR within 12 months of study start.
Median Progression-Free Survival (months)	Not Reached	13.8
	(HR = 0.48 [0.34; 0.68], p-value < 0.0001 by stratified log-rank test)
Best Overall Response‡	78.7%	74.7%
Complete Response	15.5%	18.7%
Partial Response	63.2%	56.0%
Median duration of response (months)	Not Reached	11.6

Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

14.3 Active Lupus Nephritis

Subgroup Analyses

In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6 below.

Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

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Infusion-related Reactions

Advise patients to seek immediate medical attention if signs and symptoms of infusion-related reactions occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.1 and 6.2)].

Tumor Lysis Syndrome

Advise patients to seek immediate medical attention if symptoms of tumor lysis syndrome occur [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Infections

Advise patients to seek immediate medical attention if signs of an infection occur [see Warnings and Precautions (5.6) and Adverse Reactions (6.1 and 6.2)].

Hepatitis B Virus Reactivation

Advise patients to seek immediate medical attention if symptoms of hepatitis occur [see Warnings and Precautions (5.1)]. Advise patients of the need for hepatitis B virus screening and monitoring during treatment with GAZYVA.

Progressive Multifocal Leukoencephalopathy

Advise patients to seek immediate medical attention if new or changes in neurological symptoms occur [see Warnings and Precautions (5.2)].

Neutropenia, Thrombocytopenia and Disseminated Intravascular Coagulation

Advise patients to seek immediate medical attention if signs and symptoms of bleeding or thrombosis occur. Advise patients of the need for periodic monitoring of blood counts [see Warnings and Precautions (5.7, 5.8 and 5.9) and Adverse Reactions (6.1 and 6.2)].

Immunization

Advise patients to avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.10)].

Embryo-Fetal Toxicity

Advise pregnant women of potential fetal B-cell depletion. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.2)].