SnapShots from the 2013 American Society of Hematology Abstracts – Part 5

 
Part 5. Key Biologics in Clinical Trials.
November 20, 2013
The American Society of Hematology Meeting will take place in New Orleans,
December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
In parts 1-4 we meandered through the small molecule, mainly oral drugs,
highlighting a few key pathways and focusing mainly on CLL.
Biologic drugs are a different and equally important class of therapeutics for lymphoma
treatment, and really it is Rituxan, the antibody that depletes cells expressing CD20, that
ushered in the new era of non-chemotherapy-based drugs. Some of the small molecule
trials discussed earlier were done in combination with anti-CD20 antibodies with or
without added chemotherapy. This therapeutic trend toward combination therapy will
dominate the lymphoma landscape, with chemo, targeted small molecules, and antibodies available to mix and match, just so long as they are not too toxic when combined, provide additive efficacy, and we can afford to pay for them. One might also overlay immuno-
therapy approaches – checkpoint modifiers, CAR-T modified cells, even cancer vaccines -
and of course there is also the whole bone marrow or stem cell transplantation field.
There are notable new biologics being developed for the treatment of lymphoma, and a
few of these have new data available in the ASH 2013 abstracts.
The real question is whether anything will be able to compete with the novel anti-CD20
mAb obinutuzumab.
Obinutuzumab (GA101) is aglycoengineered antibody having 10-fold greater affinity 
for FcgammaR3A. This is receptor on cytotoxic NK cells that binds to the Fc domain 
of the antibody. The binding of the Fc domain to the FcR (receptor) triggers killing of 
the target (CD20+) cell by the interacting NK cell. Obinutuzumab was approved under 
the brand name Gazyva on November 1st for use in combination with chlorambucil to 
treat patients with previously untreated CLL. This was this first drug approved under 
the FDA’s new breakthrough therapy designation and wasbased on a Phase 3 study of 
previously untreated CLL patients (n = 365) comparing Obinutuzumab plus chlorambucil 
to chlorambucil alone. The PFS for the combination therapy was 23 months compared 
with 11.1 months with chlorambucil treatment. Additional data from the Phase 3 trials, 
comparing obinutuzumab pluschlorambucil (OB-c) to rituximab (Rituxan) plus 
chlorambucil (R-c), are to be presented during the plenary session at ASH (Abstract #6). 
Those data are summarized as follows:
ORR
CR
MRD*
PFS
OB-c
78%
21%
29.4%
26.7 months
R-c
65%
7%
2.5%
15.2 months
*: MRD is minimal residual disease, meaning that bone marrow and organs are negative 
for tumor cells.
AEs were higher in the obinutuzumab plus chlorambucil arm, although it appears that 
this was due to increased severe infusion-related reactions, which can be controlled.
Another study in previously untreated CLL patients will be presented at ASH (Abstract
#523). In this trial, obinutuzumab (OB) was combined with fludarabine/cyclophosphamide 
(FC) or bendamustine (B). There are 41 patients enrolled and the median reported followup 
time is nearly 12 months. 9 patients (22%) had to discontinue treatment due to AEs, mainly cytopenias. The investigators will report and update response data, summarized here (note 
that CRi, defined as complete response with incomplete bone marrow resolution, is included 
in this table with the %PR):
ORR
CR
PR
SD
PFS
OB-FC
62%
9.5%
47.6%
19%
not reached
OB-B
90%
20%
70%
0
not reached
No responding patients progressed and PFS was not reached. While the data look very good
for efficacy, the fact that a high percentage of patients had to discontinue due to AEs is
notable.
Two other studies will be presented at ASH. One is on the treatment of CD20+ Diffuse
Large B Cell Lymphoma (DLBCL) patients in a Phase 2 clinical trial (Abstract #1820).
DLBCL is an aggressive lymphoma, currently treated with combination chemotherapy
(CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) or with rituximab plus combination chemotherapy (R-CHOP). In this trial, 80 previously untreated DLBCL
patients were treated with obinutuzumab plus CHOP. The ORR = 83%, consisting of
CR = 55% and PR = 28%. Of the 80 patients total, 11 patients discontinued treatment,
5 of these due to AEs (6.25%), but in general AEs were manageable. Nine patients had
PD, three died. These preliminary results are very encouraging, updated results including
analyses responses in DLBCL subsets (ABC v GC) and with reference to molecular
classification will be presented at the meeting. An earlier study (Abstract #1814) will
present data on the use of obinutuzumab as maintenance therapy after induction therapy
with chemo (either OB-CHOP or OB-FC). Patients had rrFL (follicular lymphoma). The
induction data was published by Radford et al. in Blood, 2013, volume 122, page 1137ff. 
CR rate was monitored at the start and end of maintenance therapy, with the maintenance 
period being a median of 35 months across the two cohorts. CR as a best overall response increased on maintenance with obinutuzumab in the OB-CHOP cohort (52%, PFS not 
reached) and in the OB-FC cohort (82%, median PFS = 46 months). Finally, a combination 
trial of obinutuzumab and ABT-199 is currently in phase Ib (NCT01685892).
These studies show benefit of obinutuzumab therapy in different lymphoma populations
using a variety of treatment paradigms, and point to the importance of this biologic
therapy in B cell lymphoma treatment.
There are a large number of new biologics competing for attention; just a few are discussed
here.
Another anti-CD20 antibody with breakthrough status is ofatumumab (Arezza). Approved in
2009 for use in rrCLL patients, this antibody is moving toward use earlier (i.e. in newly
diagnosed CLL) and in other patient subsets.
In May of this year, positive phase 3 data for ofatumumab were announced by GSK. Patients
with previously untreated CLL (n = 447) received ofatumumab plus chlorambucil (OF-C) or chlorambucil (C) alone. The study found that patients in the ofatumumab cohort experienced
a longer median PFS. That study will be updated at ASH (Abstract #528). Top line data is
here:
PFS
ORR
CR
MRD
OF-C
22 months
82%
12%
4%
C
13 months
69%
1%
0
Other studies on ofatumumab being presented at ASH include a phase 2 trial in combination
with dexamethasone, to treat high risk rrCLL patients (Abstract #2877). This study presents
a CR = 16% and PFS = 10 months, although the infection risk was quite high. Another
phase 2 study is testing the efficacy of ofatumumab in combination with the AKT inhibitor afuresertib (Abstract # 4175) in the treatment of high-risk rrCLL patients. In this small
study (n = 19) AEs were manageable (neutropenia, GI complications) but responses were
low: ORR = 42%, CR = 0, PR = 42%; 58% of patients had SD, and 26% of patients
progressed. Several other trials will also be updated (Abstracts #1645 and 4177).
An example of the high bar set by obinutuzumab therapy can be seen in several trials of
other biologics. Pfizer has developed an antibody/drug conjugate (ADC) called inotuzumab ozogamicin (InO). This is a humanized anti-CD22 antibody conjugated with calicheamicin, 
a potent cytotoxic. CD22 is expressed on most forms of NHL. The trial (Abstract #1821) 
is a phase 1 dose escalation trial designed to identify the MTD in combination with 
rituximab plus chemo (gemcitabine, dexamethasone, and cisplatin). AEs, mostly
cytopenias, causing dose reductions and dose delays established the MTD. Patients had 
rrNHL, with 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL.
At the MTD dose the ORR = 45% and the CR = 22%. Of the 55 patients enrolled, 12
(22%) discontinued due to AEs and 12 (22%) discontinued due to PD. These numbers
are a little worrisome although this is a difficult patient population to treat. It will be
important to see PFS and OS numbers as clinical development of this therapy continues.
An intriguing target for antibody development is CD37. CD37 is tetraspan protein expressed
on a variety of hematopoietic cells, and can transmit a cell death signal through its SHP-1
domain. Trubion engineered a modified antibody called TRU-016, now being developed by Emergent (see the 14 November issue of Blood – volume 122, p 3397 – for a brief description 
of this and other anti-CD37 targeting agents). Phase 2 data on TRU-016, now called 
otlertuzumab, will be presented at ASH. Otlertuzumab induces cell death directly (ie. by 
signaling cell death) and also through Fc-mediated cytotoxicity. The phase 2 trial recruited 
65 rrCLL patients who had failed between 1 and 3 prior therapies. The Abstract (#2860) 
presents data on 44 evaluable patients treated with otlertuzumab (OTL) or with otlertuzumab
plus bendamustine (OTL-b). The data are as follows:
treatment
ORR
CR
% progression
OTL
42%
4%
46
OTL-b
80%
20%
10
The % progression data refers to the responding patients only. AEs were in line with the chemotherapy treatment. A second study (Abstract #4165) provides preliminary data on
patients treated with otlertuzumab plus the anti-CD20 antibody rituximab (Rituxan). This
dual antibody therapy was given to previously untreated CLL patients. Preliminary data
suggest an ORR = 88%, and modest AEs. This trial will be updated at the meeting. These
early studies suggest that targeting CD37 is an attractive approach for CLL therapy.
BITE antibodies are bi-specific antibodies originally developed by Micromet. They have
received a lot of press following the 1.2 billion dollar acquisition of Micromet by Amgen. Blinatumomab binds to CD3 on T cells and CD19 on lymphoma cells, helping to direct the
T cells to recognize and destroy the tumor cell (BITE stands for BI-specific T cell Engager). Abstract #1811 has some very early data on blinatumomab treatment of rrDLBCL patients.
Lets be clear upfront that this is a tough patient group to treat. At the time of abstract
submission, 11 patients were enrolled with initial ORR = 57%. It will be very interesting
to hear updated results from this trial at ASH, including both efficacy and AEs, which at
first glance seem tolerable if unpleasant (including CNS toxicity).
MEDI-551 is an afucosyl-anti-CD19 antibody with augmented cytotoxic activity (due to the
lack of fucosylation of the antibody). An 83 patient Phase 1 trial (Abstract #1810) enrolled heavily pretreated rr CLL, DLBCL, FL, or MM (multiple myeloma). All of these B cell lymphoma types are CD19 positive. The ORR = 25%, with CR = 10.8% and PR = 14.5%.
50.1% of patients were characterized as SD. PFS was calculated to be 9 months. At first
glance the single agent responses are substandard; MedImmune is continuing development
of MEDI-551 in combination with chemotherapy.
A CD19 ADC has advanced to phase 2, in a combination trial with rituximab (Rituxan).
SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a cytotoxic
agent. It is under development by Sanofi and was licensed from ImmunoGen. This ADC
was given along with rituximab (Rituxan) to rrDLBLC patients (refractory to first line
therapy or relapsed after a prior therapy; Abstract #4395). ORR was low at 31% and 36%
of responders progressed by the end of the study. Sanofi plans to move this agent into
patient populations that may be more responsive.
So, here we have seen two anti-CD19 antibody therapeutics with rather poor efficacy
profiles.
I want to end with an old dog/new trick story concerning alemtuzumab. First studied many
years ago in the context of transplant rejection therapy, this anti-CD52 antibody lives on as
a treatment for hematological malignancies (CD52 is widely expressed) and, under the
brand name Lemtrada, as a therapy for multiple sclerosis. The long strange trip of this
nasty antibody (the side effect profile is not good) is the subject for another day. Of interest
at ASH however is a nice study looking at the utility of alemtuzumab for very high risk
treatment naive CLL patients (Abstract #2861). High risk is defined here genetically – these
are patients with genetic deletions or mutations known to be associated with poor prognosis. Without diving into the details, the investigators have shown that TP53 mutations had an
adverse prognostic impact and shorter PFS and this was overcome by alemtuzumab treatment. This then presents itself as a potential therapeutic for patients known to have this poor risk
factor.
If time allows I want to discuss the CAR-T technology, perhaps in the next section.