Chronic lymphocytic
leukemia (CLL) represents the most prevalent adult leukemia and the introduction
of therapeutic antibodies has increased the number of available treatments. For
both previously untreated symptomatic CLL and as salvage therapy, rituximab, a
CD20 antibody, is currently widely used in combination-based strategies. Recent
data suggest that the addition of Rituximab to Fludarabine with or without
cyclophosphamide prolongs survival in younger patients with CLL. Other improved
CD20 antibodies with promising clinical activity, include Ofatumumab and
Obinutuzumab (GA-101). Alemtuzumab, a CD52 antibody, likewise has demonstrated
benefit in both symptomatic, previously untreated CLL and in patients with
relapsed disease. Also, recent efforts to combine currently applied therapeutic
antibodies with other biologic and targeted therapies with efficacy in CLL
offers the potential to move toward alternative non-chemotherapy-based treatment
approaches (Jaglowski et al, 2010).
Laprevotte et al (2013)
reported that rituximab combined with chemotherapy is a standard treatment for
CLL. They investigated whether endogenous IL-8 affects rituximab or Obinutuzumab
(GA-101) B-leukemic depletion mediated by natural killers. Rituximab, and more
significantly Obinutuzumab, were effective in B-cell depletion and natural
killer activation using whole peripheral blood lymphocytes from untreated CLL
patients.
Obinutuzumab was approved
on November 1, 2013 by the Food and Drug Administration (FDA) for use in
combination with Chlorambucil for previously untreated CLL (NCI, 2013).
Obinutuzumab is a CD20-cytolytic antibody. The FDA labeling produced by
Genentech (2013) lists a boxed warning stating that “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”.
Dosing and administration
of Obinutuzumab includes premedication with glucocorticoid, acetaminophen and
anti-histamine. Obinutuzumab is to be diluted and administered as intravenous
infusion and is not to be administered as an intravenous push or bolus. The
recommended dose for 6 cycles (28 day cycles) is as follows: 100 mg on day 1
Cycle 1; 900 mg on day 2 Cycle 1; 1,000 mg on day 8 and 15 of Cycle 1; and 1,000
mg on day 1 of Cycles 2 through 6 (Genentech, 2013).
An FDA news release stated
that "Gazyva’s approval for CLL is based on a study of 356 participants in a
randomized open-label multi-center trial comparing Gazyva in combination with
Chlorambucil to Chlorambucil alone in participants with previously untreated
CLL...Participants receiving Gazyva in combination with Chlorambucil
demonstrated a significant improvement in progression free survival: an average
of 23 months compared with 11.1 months with Chlorambucil alone" (FDA, 2013).
National Comprehensive
Cancer Network Drug and Biologics Compendium (NCCN, 2015) indicates Obinutuzumab
(Gazyva) for the following:
§
First-line
therapy for CLL/SLL in patients with indications for treatment
o
as a single
agent or in combination with Chlorambucil for disease without del(11q) or
del(17p) in patients age ≥70 years or in younger patients with significant
comorbidities
o
in
combination with Chlorambucil for disease with del(11q) or del(17p);
§
Therapy for
CLL/SLL in patients with indications for treatment who are unable to tolerate
purine analogs as a single agent or in combination with Chlorambucil;
§
Therapy for
relapsed or refractory CLL/SLL
o
without
del(11q) or del(17p) in patients with indications for treatment
o
with
del(11q).
In an open-label,
multi-center, phase Ib study, Radford et al (2013) examined the safety and
activity of Obinutuzumab plus chemotherapy in relapsed/refractory follicular
lymphoma in 56 patients. Subjects received Obinutuzumab plus cyclophosphamide,
doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8
cycles) or Obinutuzumab plus Fludarabine and cyclophosphamide (G-FC; every 4
weeks for 4 to 6 cycles). Patients were randomly assigned to either Obinutuzumab
1,600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent
cycles or 400 mg for all doses. Treatment responders were eligible for
Obinutuzumab maintenance every 3 months for up to 2 years. Grade 1/2
infusion-related reactions (IRRs) were the most common treatment-related adverse
event (AE) (all grades: G-CHOP, 68 %; G-FC, 82 %). Grade 3/4 IRRs were rare (7
%) and restricted to the first infusion. All patients received the planned
Obinutuzumab dose. Neutropenia was the most common treatment-related hematologic
AE for G-CHOP (43 %) and G-FC (50 %). At the end of induction, a total of 96 %
(27/28) of patients who received G-CHOP (complete response [CR], 39 % [11/28])
and 93 % (26/28) of patients who received G-FC (CR, 50 % [14 of 28]) achieved
responses. The authors concluded that G-CHOP and G-FC had an acceptable safety
profile with no new or unexpected AEs, but G-FC was associated with more AEs
than G-CHOP. They stated that Obinutuzumab plus chemotherapy resulted in 93 % to
96 % response rates, supporting phase III investigation.
Morschhauser et al (2013)
noted that Obinutuzumab was superior to rituximab in human diffuse large B-cell
lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In a phase I
study by these researchers, Obinutuzumab exhibited encouraging activity but no
clear dose-response relationship, and few patients had aggressive histology’s.
In a randomized phase II study, these investigators examined the safety and
effectiveness of 2 doses of Obinutuzumab in patients with heavily pre-treated
DBLCL and MCL. Patients were randomly assigned to receive 8 cycles of
Obinutuzumab either as a flat dose of 400 mg for all infusions (days 1 and 8 of
cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800
mg on day 1 of cycles 2 to 8. A total of 40 patients were enrolled: 21 patients
in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in
the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was
28 % (32 % and 24 % in the 1,600/800-mg and 400/400-mg study arms,
respectively). Best overall response rates (ORRs) were 37 % in the 1,600/800-mg
arm and 24 % in the 400/400-mg study arm (DLBCL, 8 [32 %] of 25 patients; MCL, 4
[27 %] of 15 patients). Five (20 %) of 25 rituximab-refractory patients
exhibited treatment response, including 4 of 12 in the 1,600/800-mg group. The
most common AEs were IRRs, which were manageable; 3 patients had grade 3/4 IRRs;
grade 3/4 neutropenia was seen in only 1 patient. The authors concluded that
Obinutuzumab 1,600/800 mg achieved early steady-state concentration and clinical
activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL,
supporting further exploration.
Cameron and McCormack
(2014) stated that Obinutuzumab is an intravenously administered, humanized and
glyco-engineered, type II anti-CD20 monoclonal antibody for the treatment of
B-cell malignancies. It is approved in the U.S. for use in combination with
Chlorambucil for the first-line treatment of CLL, and has been filed for
approval in the EU in this indication. The antibody is based on GlycArt
Biotechnology`s (later Roche GlycArt AG) proprietary GlycoMAb® technology, which
uses glycol-engineered antibodies that specifically increase antibody-dependent
cellular cytotoxicity and thereby increase immune-mediated target cell death.
Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell
death. The monoclonal antibody is in world-wide phase III development with Roche
and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen
Idec, for DLBCL and non-Hodgkin`s lymphoma (NHL) generally, and is also in phase
III development in countries outside of the U.S. and EU for CLL.
An Up-to-date review on
“Treatment of relapsed or refractory diffuse large B cell lymphoma” (Freedman
and Friedberg, 2014) states that “CLINICAL TRIALS -- Often there is no better
therapy to offer a patient than enrollment onto a well-designed, scientifically
valid, peer-reviewed clinical trial. Additional information and instructions for
referring a patient to an appropriate research center can be obtained from the
United States National Institutes of Health (www.clinicaltrials.gov). Areas of
active study include novel agents such as Obinutuzumab, Everolimus, PI3 kinase
inhibitors, aurora A kinase inhibitors, and syk inhibitors”.
Furthermore, NCCN’s Drugs
& Biologics Compendium (2014) does not list large B-cell lymphoma/DLBCL as a
recommended indication of Obinutuzumab.
In the phase II part of
the phase I/II GAUGUIN study, Salles et al (2013) evaluated the safety and
effectiveness of 2 different doses of Obinutuzumab in patients with
relapsed/refractory indolent NHL. Patients were randomly assigned to receive 8
cycles of Obinutuzumab as a flat dose of 400 mg on days 1 and 8 of cycle 1 and
also on day 1 of cycles 2 to 8 (400/400 mg) or 1,600 mg on days 1 and 8 of cycle
1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800 mg). A total of 40 patients
were enrolled, including 34 with follicular lymphoma; 38 of 40 patients had
previously received rituximab and 22 of 40 were rituximab refractory. The ORR at
the end of treatment was 55 % (95 % CI: 32 % to 76%) in the 1,600/800-mg group
(9 % complete responders) and 17 % (95 % CI: 4 % to 41 %) in the 400/400-mg
group (no complete responders). Five of 10 rituximab-refractory patients had an
end-of-treatment response in the 1,600/800-mg group versus 1 of 12 in the
400/400-mg group. Median progression-free survival (PFS) was 11.9 months in the
1,600/800-mg group (range of 1.8 to 33.9+ months) and 6.0 months in the
400/400-mg group (range of 1.0 to 33.9+ months). The most common AEs were IRRs
seen in 73 % of patients, but only 2 patients had grade 3 to 4 IRRs (both in the
1,600/800-mg group). No IRRs were considered serious, and no patients withdrew
for IRRs. The authors concluded that the 1,600/800-mg dose schedule of
Obinutuzumab has encouraging activity with an acceptable safety profile in
relapsed/refractory indolent NHL.
Owen and Stewart (2014)
analyzed data for the use of Obinutuzumab in the treatment of CD20(+)
lympho-proliferative disorders with a focus on CLL. Targeted therapy against
CD20 with the mAb rituximab led to significant improvements in survival for
patients with B-cell NHL and is the current mainstay of treatment for CD20(+)
malignancies. Despite this, many patients relapse or become refractory after
rituximab-containing therapies, so efforts have been made to develop better
anti-CD20 mAbs. Obinutuzumab recently demonstrated superiority over rituximab in
the only published phase III study comparing the 2 antibodies. The authors
concluded that the demonstration of superiority of Obinutuzumab over rituximab
in the CLL11 phase III study is potentially practice-changing. Obinutuzumab has
also proven safe and effective in CD20(+) NHL in phase I/II studies and results
of phase III studies in NHL are eagerly awaited.