CLINICAL NEWS
On Location 2018 ASH Annual Meeting
As of August 17, 2018 (data cutoff),
five patients (4.1%) remained on treat-
ment. The most common reasons for
discontinuation were: disease progression
(55.1%) and adverse events (AEs; 32.2%).
At three-month follow-up, the overall
response rate (ORR; primary endpoint)
was 26.2 percent, including:
• partial response (PR): 19.7%
• very good PR (VGPR): 4.9%
• stringent complete response (sCR):
1.6%
The two patients who achieved sCRs also
had minimal residual disease–negative
status, the authors reported, and an ad-
ditional 13.1 percent of patients achieved
a minimal response (MR). Dr. Chari
noted that the time to response was “quite
short – only one month – and the median
duration of response was 4.4 months.”
In subgroup analyses, response rates
were similar, regardless of the last prior
therapy.
The median progression-free survival
(PFS) and overall survival (OS) were 3.7
months and 8.6 months, respectively
( TABLE 4 ). Importantly, Dr. Chari said,
“the median overall survival was 15.6
months for both patients who achieved
a minimal response or a partial response
– highlighting the importance of looking
at both partial and minimal responses in
heavily pretreated patient populations.”
Median duration of selinexor treat-
ment was 9 weeks (range = 1-60+ weeks),
and 79.7 percent of patients required a
dose modification – most of which oc-
curred in the first two cycles. The most
common non-hematologic AEs included
nausea, fatigue, weight loss, anorexia,
vomiting, and diarrhea. The most com-
mon hematologic AE was thrombocyto-
penia (67.5%), followed by anemia (48%).
AEs were generally reversible, and the
investigators found that the side effects
of selinexor were dose- and schedule-
TABLE 4.
Survival Estimates According to Treatment Response
All Patients
(n=122) ≥PR
(n=32) ≥MR
(n=48) SD
(n=48) PD/NE
(n=26)
Median
progression-free
survival 3.7 months 5.3 months 4.6 months 2.8 months 1.1 months
Median overall
survival 8.6 months 15.6 months 15.6 months 5.9 months 1.7 months
PR = partial response; MR = minimal response; SD = stable disease; PD = progressive disease; NE =
not estimable
dependent. Because selinexor crosses
the blood-brain barrier, they stressed
the importance of early identification,
frequent assessment, and implementa-
tion of supportive care measures for AE
management.
Limitations of the study include the
lack of a comparator or placebo arm, as
well as a relatively small number of par-
ticipants included in the final cohort. Dr.
Chari added that ongoing studies are inves-
tigating potential biomarkers of selinexor
resistance, as well as selinexor in combina-
tion with various MM backbone agents.
The authors report financial relation-
ships with Novartis, Array Biopharma,
Celgene, Amgen, Pharmacyclics, Takeda,
Janssen, Millennium Takeda, Bristol-Myers
Squibb, Sanofi, Jazz Pharmaceuticals, and
Karyopharm Therapeutics (which spon-
sored the trial).
REFERENCE
Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM
study (part 2) in penta-refractory multiple myeloma (MM): deep and
durable responses with oral selinexor plus low dose dexamethasone in
patients with penta-refractory MM. Abstract #598. Presented at the
2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.
ECHELON-2: Brentuximab Vedotin Combination Outperforms CHOP
for Peripheral T-Cell Lymphomas
Results from the phase III ECHELON-2
trial showed that brentuximab vedotin
added to a combination of cyclophos-
phamide, doxorubicin, and prednisone
(BV+CHP) nearly doubled progression-
free survival (PFS) for patients with
peripheral T-cell lymphomas (PTCLs),
compared with treatment involving a
standard regimen of cyclophosphamide,
doxorubicin, vincristine, and prednisone
(CHOP).
Steven Horwitz, MD, from the
Memorial Sloan Kettering Cancer Center
in New York, presented the results at the
2018 ASH Annual Meeting.
“CHOP and CHOP-like regimens are
the most common frontline treatments
of PTCL, but these regimens do not pro-
duce a durable remission in the majority
of [PTCL] subtypes, including ALK-
positive systemic anaplastic large cell
lymphoma (sALCL) and other CD30-
positive PTCLs,” Dr. Horwitz explained.
“ECHELON-2 is the first prospective
trial in peripheral T-cell lymphoma to
show an overall benefit over CHOP,
[with a] 29-percent reduction in the risk
of disease progression and a 34-percent
reduction in the risk of death.”
Based on these data, the U.S. Food and
Drug Administration expanded brentux-
imab vedotin’s indication in November
2018 to include the firstline treatment of
adult patients with PTCLs – marking the
first approval for this indication.
The double-blind, randomized, multi-
center ECHELON-2 trial enrolled 452
38
ASH Clinical News
patients from 132 sites in 17 countries.
All participants had newly diagnosed,
CD30-positive PTCLs and an Eastern
Cooperative Oncology Group perfor-
mance status score of ≤2. People with
a history of other primary invasive
malignancy or progressive multifocal
leukoencephalopathy were excluded
from the trial.
After stratifying patients according
to histologic subtype and International
Prognostic Index score, investigators
randomly assigned patients to receive six
to eight 21-day cycles of either:
• BV+CHP: brentuximab vedotin
1.8 mg/kg plus cyclophosphamide
750 mg/m 2 , doxorubicin 50 mg/m 2 ,
and prednisone 100 mg on days 1-5
(n=226)
• CHOP: cyclophosphamide 750 mg/m 2 ,
doxorubicin 50 mg/m 2 , vincristine 1.4
mg/m 2 , and prednisone 100 mg on
days 1-5 (n=226)
The researchers reported that baseline
characteristics were similar between
both arms: The median age was 58 years
(range not reported) and most patients
had stage III/IV disease. sALCL was the
most common PTCL subtype (70%), fol-
lowed by PTCL-not otherwise specified
(16%) and angio-immunoblastic T-cell
lymphoma (12%).
As of August 15, 2018 (data cutoff),
449 of the 452 randomized patients
received at least one dose of study
treatment. Most of the patients –85
percent and 79 percent of patients in the
BV+CHP and CHOP groups, respec-
tively – completed treatment. In the
BV+CHP group, discontinuation was
most often related to adverse events
(AEs; 7%) or disease progression (3%); in
the CHOP group, most patients discon-
tinued due to disease progression (12%)
and AEs (7%).
After a median follow-up of 36.2
months (range not reported), 83 per-
cent of BV+CHP-treated participants
responded, compared with 72 percent of
CHOP-treated participants (p=0.003),
and complete responses were more
common in the BV+CHP group (68%
vs. 56%; p=0.007). “The superiority
of [BV+CHP] is not due to the poor
response of CHOP, as the CHOP curves
were better than anticipated or histori-
cally reported,” Dr. Horwitz clarified.
The median PFS (primary endpoint)
was 48.2 months (range = 35.2 months
to not evaluable) in the BV+CHP group
and 20.8 months (range = 12.7-47.6
months) in the CHOP group. This trans-
lated to a 29-percent lower risk of disease
progression or death with BV+CHP
(hazard ratio = 0.71; 95% CI 0.54-0.93;
p=0.01).
The rate of three-year PFS also ap-
peared to be higher in the BV+CHP
group (57% vs. 44%; p value not
provided).
Median overall survival (OS;
secondary endpoint) also appeared to
be higher in the BV+CHP group (not
reached vs. 17.5 months; ranges and p
value not reported).
The incidence of AEs was consistent
between groups, and with the known
safety profiles of each treatment regimen,
the researchers added. Nearly all patients
in each arm experienced an AE (99% for
BV+CHP and 98% for CHOP). The most
common treatment-related AEs were
nausea (46% for BV+CHP and 38% for
CHOP), peripheral sensory neuropathy
(45% and 41%), and neutropenia (38% in
each arm). Grade ≥3 AEs reported in the
BV+CHP group included neutropenia
(33%), febrile neutropenia (17%), and
anemia (12%).
AEs were fatal for seven patients (3%)
on the brentuximab vedotin arm and
nine (4%) on the CHOP arm.
Patients with ALK-positive sALCL
generally saw the greatest improvement
in PFS and OS with BV+CHP over
CHOP, Dr. Horwitz reported, but he
noted the study was not powered to com-
pare efficacy among individual subtypes,
which may be a limitation of the analysis.
The authors reported financial rela-
tionships with Seattle Genetics, which
sponsored the trial. ●
REFERENCE
Horwitz S, O’Connor O, Pro B, et al. The ECHELON-2 trial: results
of a randomized, double-blind, active-controlled phase 3 study of
brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline
treatment of patients with CD30+ peripheral T-cell lymphomas.
Abstract #997. Presented at the 2018 ASH Annual Meeting, December
3, 2018; San Diego, CA.
January 2019 Annual Meeting Edition