Clinical News
On Location ASH Meeting on Lymphoma Biology
then, additional data on
progression-free survival
and overall survival have
verified the clinical benefit of the drug in these
patients.
“Ibrutinib is, at least
currently, the blockbuster monotherapy
in multiple lymphoid
malignancies, including chronic lymphoid
leukemia, mantle cell
lymphoma, and ABC
DLBCL,” Dr. Shaffer
told ASH Clinical News.
“In some patients, it is
practically curative, but
what we are seeing, because it is in such wide
use, are patients whose
tumors are resisting this
therapy.”
According to Dr. Shaffer, investigators have a
large armamentarium of
molecular tools that can
be used to elucidate the
mechanisms of ibrutinib
resistance. Prior research
has already shown that
ibrutinib resistance may
arise due to a mutation
of cysteine residues in
the active site of BTK —
Arthur L. Shaffer III, PhD
to which ibrutinib binds.
Dr. Shaffer and
colleagues developed
multiple, independent
ibrutinib-resistant ABC
DLBCL cell line models
to more fully explore
possible mechanisms of
ibrutinib resistance.
Using these cell lines,
Dr. Shaffer and colleagues found one ABC
DLBCL model that had
mutated BTK in its active site, but not at the
cysteine normally mutated in resistant cells;
this mutant, in addition to disrupting ibrutinib
binding, may be an activating mutation of BTK
that promotes lymphoma cell survival. In addition, the investigators found that the majority
of ibrutinib-resistant ABC DLBCL models did
not mutate BTK, but seemed to up-regulate
other potentially druggable survival pathways to
circumvent the effects of ibrutinib.
“We hope that this research will quickly
shorten the practical time between the clinic and
the bench, and back into the clinic,” Dr. Shaffer said. “We have a host of other drugs that hit
other important pathways in lymphomas, and,
hopefully, by applying one or more of those as
a single agent or in combination with ibrutinib,
we will be able to treat resistance as soon as we
detect it.”
Mechanisms of Ibrutinib
Resistance Varied in
ABC DLBCL
Lymphoma cells may develop resistance to the
Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib
using a variety of potentially druggable pathways,
opening the door to finding more effective singleagent or combination secondary therapies for
patients with the activated B-cell–like diffuse large
B-cell lymphoma (ABC DLBCL) subtype who
develop resistance to the drug.
Data about these pathways to new therapeutic
options were presented by Arthur L. Shaffer III,
PhD, a staff scientist in the Lymphoid Malignancies Branch of the Center for Cancer Research at
the National Cancer Institute.
In 2013, ibrutinib was approved for patients
with mantle cell lymphoma who have had at
least one prior therapy. Early in 2014, the Food
and Drug Administration granted ibrutinib accelerated approval to treat patients with chronic
lymphocytic leukemia, as well as patients with
chronic lymphocytic leukemia who carry a
deletion in chromosome 17, based on trial
results showing improved overall response
rates in patients treated with the drug. Since
26
ASH Clinical News
Shaffer AL. Mechanisms of ibrutinib resistance in the aggressive, ABC-subtype of
diffuse large B-cell lymphoma: pathways to new therapeutics options. Presented at:
ASH Meeting on Lymphoma Biology; August 10–13; Colorado Springs, CO.
Early Data Show EZH2
Inhibitor Active in NonHodgkin Lymphoma
The EZH2 inhibitor EPZ-6438 appears to be a well-tolerated drug and is showing early evidence of anti-lymphoma activity in patients with non-Hodgkin lymphoma of varying histology, according to early observations
from a phase I clinical trial presented at the first ASH
Meeting on Lymphoma Biology.
EZH2 is a histone methyltransferase that is implicated
as an oncogenic driver of multiple human cancers, according to Robert A. Copeland, PhD, chief scientific
officer of Epizyme, the developer of EPZ-6438.
“EZH2, and the protein methyltransferases in general, represents a novel target class with strong cancer
associations,” Dr. Copeland told ASH Clinical News. “The
compound EZP-6438 represents the first potent, selective,
and orally bioavailable inhibitor of EZH2 to enter human
clinical trials.”
To date, the ongoing phase I study has completed
analysis of three cohorts of patients:
• six patients enrolled at a dose of 100 mg twice
daily
• three patients at 200 mg twice daily
• three patients at 400 mg twice daily
Enrollment of two additional cohorts testing doses of 800
mg and 1,600 mg is ongoing.
Among the 12 evaluable patients, four of whom have
non-Hodgkin lymphoma of varying histology, the maximum tolerated dose had not been reached, and patients
did not experience any dose-limiting toxicities or discontinue treatment due to adverse events.
Two patients with non-Hodgkin lymphoma achieved
partial responses, one patient with relapsed transformed
germinal center diffuse large B-cell lymphoma dosed at
100 mg and one patient with primary refractory mediastinal B-cell lymphoma receiving 200 mg of the drug. Both
of these patients had wild-type EZH2. In addition, one
patient with follicular lymphoma and the EZH2 mutation
achieved stable disease at a 400 mg dose.
In preclinical testing, EPZ-6438 combined with CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone) showed increased potency and activity in cell lines,
independent of EZH2-mutant status. Dr. Copeland and
colleagues hypothesize that much of the synergy between
these two treatments was due to prednisone, a glucocorticoid receptor agonist.
Based on the promising results seen in the phase
I dose-escalation study, phase II studies testing
EPZ-6438 alone and in combination with steroids
in patients with germinal center diffuse large B-cell
lymphoma, primary refractory mediastinal B-cell
lymphoma, and follicular lymphoma with and without
EZH2 mutations, will be initiated.
“If we continue to see objective responses in nonHodgkin lymphoma patients in a fashion that is independent of EZH2 mutation, EZH2 inhibitors could have
broad utility across a variety of B-cell lymphomas,” Dr.
Copeland said.
Copeland RA. Activity of the EZH2 inhibitor EPZ-6438 (E7438) in non-Hodgkin lymphoma:
preclinical models and early clinical observations. Prese nted at: ASH Meeting on Lymphoma
Biology; August 10-13; Colorado Springs, CO.
October 2014