July 31, 2016
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Gazyva

"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

 

CLL is a blood and bone ma"...

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Gazyva

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

In clinical trials in patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B-cell counts < 0.07 x 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.

Cardiac Electrophysiology

The potential effects of GAZYVA on the QTc interval have not been studied.

Pharmacokinetics

The elimination of obinutuzumab is comprised of a linear clearance pathway and a time-dependent non-linear clearance pathway. As GAZYVA treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target-mediated drug disposition (TMDD) and saturation of the TMDD at the end of the treatment cycle at the proposed clinical dose regimen. Based on a population pharmacokinetic analysis, in patients with CLL the geometric mean (CV%) obinutuzumab volume of distribution at steady state, clearance after TMDD saturation and terminal half-life are approximately 4.1 (20%) L, 0.11 (53%) L/day and 26.4 (48%) days, respectively. In patients with iNHL the geometric mean (CV%) obinutuzumab volume of distribution at steady state, clearance after TMDD saturation and terminal half-life are approximately 4.3 (22%) L, 0.08 (45%) L/day and 36.8 (40%) days, respectively.

Specific Populations

Age: Age did not affect the pharmacokinetics of GAZYVA.

Body Weight: Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification.

Renal Impairment: Based on the population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min.

Hepatic Impairment: GAZYVA has not been studied in patients with hepatic impairment.

Clinical Studies

Chronic Lymphocytic Leukemia

GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (Study 1) in 781 patients with previously untreated CD20+ chronic lymphocytic leukemia requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) < 70 mL/min. Patients with CrCl < 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 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 1000 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], 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 Study 1, the median age was 73 years, 62% were male, and 95% were Caucasian. Sixty-five percent had a CrCl < 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 CrCl 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 treated arm and 67% in the chlorambucil alone arm.

In the Stage 1 analysis of Study 1, 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 Study 1, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab 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 arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm and 4 patients (12%) in the rituximab arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

Efficacy results are shown in Table 8, and the Kaplan-Meier curves for Stage 1a Overall Survival and Stage 2 PFS are shown in Figures 1 and 2, respectively.

Table 8 : Efficacy Results for Study 1

Endpoint Stage 1 of Study 1 Stage 2 of Study 1
GAZYVA + Chlorambucil*
n = 238
Chlorambucil
n = 118
GAZYVA + Chlorambucil*
n = 333
Rituximab + Chlorambucil
n = 330
Median Progression-Free Survivala 27.2 months 11.2 months (HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test) 26.7 months 14.9 months (HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
Overall Response Rateb 78.2% 33.1% 79.6% 66.3%
  Complete Response 28.2% 0 26.1% 8.8%
  Complete Response with Incomplete Marrow Recovery 2.5% 1.7% 2.1% 1.5%
  Partial Response 45.0% 30.5% 48.6% 54.1%
  Nodular Partial Response 2.5% 0.8% 2.7% 1.8%
  Median Duration of Response 22.4 months 4.7 months 19.6 months 9.7 months
Overall Survival HR 0.41 [0.23; 0.74] Not Yet Mature
aAs defined by independent review. Investigator-assessed PFS was consistent with data from independent review.
bDefined as best overall response rate (ORR = CR + CRi + PR + nPR).
*All Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).

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

Kaplan-Meier Curve of Overall Survival in Patients with CLL in Study 1 -  Illustration

Figure 2 : Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in Study 1 (Stage 2)

Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in Study 1 -  Illustration

Follicular Lymphoma

Study 2 is an open-label, multicenter, randomized study including 321 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab or a rituximab-containing regimen. These patients were randomized to receive either bendamustine alone (n = 166) or GAZYVA in combination with bendamustine (n = 155) 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 rituximab-refractory type (refractory to prior rituximab monotherapy versus rituximab in combination with chemotherapy) and the number of prior therapies ( ≤ 2 versus > 2).

GAZYVA was given by intravenous infusion as a flat dose of 1000 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.

In Study 2, patients had a median age of 63 years, 88% were Caucasian, 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 monotherapy, 37% of patients were refractory to prior rituximab plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab maintenance treatment received following rituximab plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab and an alkylating agent during any prior regimen (double refractory).

The primary objective of the study was to evaluate progression-free survival as determined by an independent review committee (IRC). 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 9. Kaplan-Meier curves for PFS are shown in Figure 3.

An analysis conducted with 24.1 months of median observation time revealed that the median overall survival was not yet reached in either arm. Kaplan-Meier curves for OS are shown in Figure 4.

Table 9 : Efficacy Results from Study 2a,b

Endpoint Study 2
GAZYVA + Bendamustine followed by GAZYVA monotherapy
n = 155
Bendamustine
n = 166
Median Progression-Free Survival NR 13.8 months (HR = 0.48 [0.34; 0.68], p-value < 0.0001 stratified log-rank test)
Best Overall Responsec 78.7% 74.7%
  Complete Response  15.5% 18.7%
  Partial Response 63.2% 56.0%
Median duration of DOR (months) NR 11.6 months
aBased on FL population.
bAs defined by independent review.
cBest response of CR/PR within 12 months of study start.

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

GAZYVA® (obinutuzumab) Figure 3 Illustration

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

Kaplan-Meier Curve of Overall Survival in Patients with FL - Illustration

Last reviewed on RxList: 3/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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