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Neratinib shows consistent breast cancer benefit at 3 years
BY BRUCE JANCIN
Frontline Medical News
T
he investigational oral tyrosine
kinase inhibitor neratinib showed
continued benefit in terms of re-
duced invasive disease-free survival
at 3 years of follow-up in women with
early-stage HER2-positive breast
cancer in the randomised, double-
blind ExteNET trial, DrArlene Chan
reported at the San Antonio Breast
Cancer Symposium.
The 3-year analysis was not
prespecified. It was performed be-
cause she and her coinvestigators
were concerned that the previously
reported benefit seen at 2 years
might be lost with longer follow-up,
as has occurred with trastuzumab
in the landmark HERA (HERcep-
tin Adjuvant) trial. Reassuringly,
however, the absolute 2.3% benefit
for neratinib compared to placebo
seen at 2 years in ExteNET was
maintained at 3 years in the up-
dated analysis, where the absolute
difference remained essentially
unchanged at 2.1%, according to
Dr Chan, vice chair of the Breast
Cancer Research Centre of Western
Australia in Perth.
Moreover, most patients have
reached the 4-year mark in follow-
up, where the invasive disease-free
survival benefit has remained sig-
nificant in favour of neratinib at
90.5% versus 88.6% with placebo,
she added.
ExteNET was a large international
trial of 2,840 women with stage II-
IIIc HER2-positive breast cancer
with node-positive disease who
were randomised to oral neratinib
at 240 mg/day or placebo for 1 year
beginning an average of 4.4 months
after completing adjuvant chemo-
therapy and 1 year of trastuzumab.
The impetus for ExteNET was
the well-established observation
that relapse occurs in up to 26%
of trastuzumab-treated patients
at 8-plus years of follow-up. The
study hypothesis is that neratinib, a
tyrosine kinase inhibitor of HER1,
–2, and –4, will prevent or delay dis-
ease recurrence because it attacks
the cancer through a mechanism
of action different from that of
trastuzumab.
At 2 years of follow-up post
neratinib, the invasive disease-free
survival rate was 93.9% with active
therapy and 91.6% with placebo, as
previously reported by Dr Chan. At 3
years in the roughly 85% of patients
who remained in the study, which
changed sponsors in the interim, the
rates were 92% and 89.9%.
The 3-year outcomes were most
robust in patients who began neratin-
ib less than 1 year after completing
trastuzumab and who were hormone
receptor-positive. In this subgroup,
the 3-year invasive disease-free sur-
vival rate was 93.3% with neratinib
versus 88.6% with placebo. That, Dr
Chan said, is the scenario where de-
layed adjuvant neratinib might prove
beneficial in clinical practice.
Patients with hormone receptor-
negative disease didn’t benefit from
neratinib.
Forty percent of patients on ner-
atinib developed grade 3 diarrhoea,
the agent’s major side effect and one
that is a class effect with the tyros-
ine kinase inhibitors. Most cases
occurred within the first 30 days of
treatment and lasted for a median
of 5 days, with 1.4% of neratinib-
treated patients being hospitalised
for this complication.
Dr Chan noted that the study
protocol precluded prophylaxis with
loperamide during the first month
of neratinib, which has been shown
by other investigators to markedly
reduce the frequency and severity
of diarrhoea.
Another ExteNET follow-up is
planned at the 5-year mark.
Audience members asked how the
United States Food and DrugAdmin-
istration’s approval of pertuzumab
with indications for neoadjuvant treat-
ment of HER2-positive breast cancer
as well as for metastatic disease will
change the prospects for neratinib.
Dr Chan replied that, like
other medical oncologists, she’s
eagerly awaiting the results of the
APHINITY trial, which is testing
adjuvant pertuzumab versus pla-
cebo on top of chemotherapy plus
trastuzumab in women with HER2-
positive disease.
“I would suspect that even if
APHINITY is positive, there will
be patients who will still have a
risk of relapse, so we still won’t be
curing all HER2-positive patients,”
she said, adding that a new clinical
trial would be required in order to
establish that neratinib is of benefit
in such individuals.
CREATE-X – Capecitabine is efficacious against
residual HER2-negative breast cancer
BY SUSAN LONDON
Frontline Medical News
A
djuvant capecitabine improves
outcomes in women with HER2-
negative breast cancer who still
have invasive disease after neoadju-
vant chemotherapy, according to find-
ings of the CREATE-X trial reported
at the San Antonio Breast Cancer
Symposium.
“Patients with pathologic residual
invasive disease after neoadjuvant
chemotherapy have a higher risk
for relapse,” said presenting author
Dr Masakazu Toi, a professor at
Kyoto University Hospital in Japan,
and founder and senior director of the
Japan Breast Cancer Research Group
(JBCRG). But “it is unclear whether
postoperative systemic chemotherapy
following neoadjuvant chemotherapy
is able to prolong survival.”
The phase III trial was conducted
among 910 patients with early breast
cancer in Japan and Korea who still
had positive nodes or didn’t achieve
a pathologic complete response after
receipt of neoadjuvant chemotherapy
that included an anthracycline, a tax-
ane, or both. They were randomised
to open-label adjuvant capecitabine
or no capecitabine, in addition to
standard therapy.
Results of a preplanned 2-year in-
terim analysis, reported in a session
and related press briefing, showed
that the risk of disease-free survival
events was 30% lower and the risk of
death was 40% lower among women
given capecitabine than among coun-
terparts not given the drug, prompting
early stopping of the trial.
The disease-free survival results
were similar in subgroup analyses.
In particular, benefit was similar in
patients with triple-negative disease,
who historically haven’t fared well on
this drug.
“The balance of benefit and toxicity
would favour the use of capecitabine
in [this] post-neoadjuvant chemo-
therapy situation, but prediction for
therapeutic benefit needs to be in-
vestigated further,” Dr Toi concluded.
“The cost-effectiveness analysis will
be carried out soon,” he added.
Press briefing moderator Dr Virgin-
ia Kaklamani, codirector of the San
Antonio Breast Cancer Symposium,
as well as professor of medicine in the
division of haematology/oncology at
the University of Texas, San Antonio,
and leader of the Breast Cancer Pro-
gram, Cancer Therapy & Research
Centre there, wondered if the results
are practice-changing.
“On Monday morning, when I see a
patient who has residual disease after
neoadjuvant chemotherapy, what do I
tell her?” she asked.
“I think we need to take care of the
reimbursement issue,” Dr Toi replied,
referring to the current lack of the
United States Food and Drug Ad-
ministration approval of capecitabine
for this indication. “But personally, I
would like to consider this treatment.”
In the session where the findings
were presented, some attendees
expressed skepticism about the ob-
served benefit of capecitabine, given
previous studies.
This benefit may have been due in
part to the fact that in CREATE-X,
capecitabine was given largely be-
cause it does not have cross-resist-
ance with anthracyclines and taxanes,
Dr Toi speculated.
Attendee Dr Steven Vogl, an on-
cologist at the Montefiore Medical
Centre in New York, proposed that
the findings may have different
implications for women with oestro-
gen receptor-positive versus triple-
negative disease, based on both their
likelihood of pathologic complete
response (pCR)and the prognostic
impact of that response.
“I put it to you that really what
this tells us is if we have a triple-
negative patient who doesn’t achieve
pCR after good neoadjuvant therapy,
this [capecitabine] is probably a
reasonable option, even though it’s
quite toxic, and certainly should be
explored further,” he said. “I’m not
sure I would go home and treat my
ER-positive patients who don’t get a
pCR with capecitabine based on this
study.”
In the trial, the 2-year disease-free
survival rate – the trial’s primary end-
point – was 82.8% with capecitabine
and 74.0% without it. The estimated
5-year rates were 74.1% and 67.7%,
respectively (hazard ratio, 0.70; P =
0.005).
Furthermore, the 2-year overall sur-
vival rate was 94% with capecitabine
and 89.2% without it. The estimated
5-year rates were 89.2% and 83.9%,
respectively (HR, 0.60; P < 0.01).
Patients in the capecitabine arm
were more likely to experience grade
3 or worse neutropenia (7% vs 2%)
and diarrhoea (3% vs < 1%). And 11%
developed grade 3 hand-foot syndrome.
However, these toxicities weremanage-
able, according to the investigators.
Dr Toi disclosed that he receives a re-
search grant fromChugai Pharmaceuti-
cal Company. The trial was supported
by a grant from Specified Nonprofit
Corporation – Advanced Clinical Re-
search Organization (ACRO) and other
donations to the Japan Breast Cancer
Research Group.
Can aspirin prevent breast cancer?
BY BRUCE JANCIN
Frontline Medical News
A
large randomised controlled trial of aspirin for breast cancer prevention
is warranted in light of new evidence that aspirin use shows a strong
independent inverse relationship with mammographic breast density,
Dr Marie E. Wood declared at the SanAntonio Breast Cancer Symposium.
Breast density, she noted, is well accepted as a modifiable risk factor for
both oestrogen receptor-negative (ER–) and oestrogren receptor-positive
(ER+) breast cancer.
“Aspirin could be a promising breast cancer prevention therapy. It is
cheap, safe, well tolerated, and there is strong biologic and epidemiologic
evidence for a prevention effect for both ER– and ER+ breast cancers,”
said Dr Wood, professor of medicine and director of the familial cancer
program at the University of Vermont in Burlington.
There is an unmet need for better chemoprevention agents for breast
cancer. The current ones, such as tamoxifen and raloxifene, don’t prevent
ER– breast cancer. Plus, they have substantial side effects leading to
low utilisation for primary prevention, she continued.
Dr Wood presented a retrospective study of 26,000 women that
demonstrated a dose-response relationship between aspirin use and
lower mammographic breast density. The relationship was stronger in
women under age 60 years and inAfricanAmericans. That’s an important
finding because those two groups are at increased risk for developing
ER– breast cancer.
She and her coinvestigators reviewed the electronic medical records
of 26,000 women in 36 primary care and ob.gyn. practices. All had
undergone routine screening mammography during 2012-2013 and had
an office visit in the prior year that included gathering a confirmed list
of medications.
The study group included 5111 aspirin users and 20,889 nonusers. After
performing logistic regression analysis to adjust for differences between the
two groups in terms of age, ethnicity, and body mass index, the investiga-
tors examined the association between aspirin use and BI-RADS (Breast
Imaging Reporting and Data System) breast density. The prevalence of
low-risk, entirely fatty breasts was 9.6% in aspirin nonusers, compared
with 16.9% in aspirin users, while extremely dense breasts were present
in 5.1% of nonusers versus just 1.6% of aspirin users, Dr Wood reported.
Women taking aspirin at 300 mg/day or less were 16% less likely to
have mammographically dense breasts – that is, BIRADS 3 or 4 – than
were aspirin nonusers. Women on more than 300 mg/day were 38% less
likely to have dense breasts than nonusers.
Previous clinical trials looking at aspirin for breast cancer prevention
have had design flaws that compromised the findings. Moreover, the
several prior studies examining a link between aspirin use and mam-
mographic breast density either lumped all NSAIDs together or were
limited by small sample size, according to the oncologist.
As a next step in this project, Dr Wood and her coinvestigators plan to
examine duration of aspirin use and its relationship to mammographic
breast density in this study population.
The 3-year outcomes were most robust in patients who began
neratinib less than 1 year after completing trastuzumab and
who were hormone receptor-positive. That is the scenario
where delayed adjuvant neratinib might prove beneficial in
clinical practice.
H
aematology
& O
ncology
N
ews
• Vol. 9 • No. 1 • 2016
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