1. health and fitness
2. disease
3. cancer

MAY 2015
Volume 11
Number 5
oncologyreport.com
LUNG CANCER
GYNECOLOGIC MALIGNANCIES
GASTROINTESTINAL MALIGNANCIES
BREAST CANCER
MELANOMA
GYNECOLOGIC MALIGNANCIES
GASTROINTESTINAL
32 Personalized
PD-L1 blockade
breaks through
triple-negative
breast cancer
©Brian Chase/Thinkstock.com
2
May 2015 • The Oncology Report
ELCC: Tumor DNA from urine shows
high testing promise
VITALS
LUNG CANCER
Key clinical point: Urine
showed potential as a fully
noninvasive source for circulating tumor DNA with high
testing concordance compared
with tumor-biopsy DNA in initial clinical experience with 34
lung cancer patients.
Major finding: Urine circulating
tumor DNA had overall concordance of 97% compared
with tumor-biopsy DNA for
detecting treatment-altering
mutations.
Data source: Single-center
study of 34 patients with
advanced non-small cell lung
cancer.
Disclosures: The study was
sponsored by Trovagene, the
company developing the tests
used in the study. Several
coauthors on the study are Trovagene employees. Dr. Husain
had no personal disclosures.
DR. HATIM HUSAIN
BY MITCHEL L. ZOLER
AT E LC C 2 0 1 5
GENEVA – Blood sampling provides a
less invasive alternative to tumor biopsy
for collecting cancer DNA for mutation
testing, but retrieving tumor DNA from
a patient’s urine is least invasive of all.
In an early phase of clinical investigation, researchers assessed the feasibility
of using urine to collect cell-free tumor
DNA to detect mutations in 34 patients
with advanced non–small cell lung cancer. The results suggested that testing
circulating tumor (ct) DNA isolated
from patients’ urine was sensitive compared with testing DNA from biopsied
specimens of the primary tumor, and
it was able to flag tumor changes early,
before clinically-identifiable effects appeared, Dr. Hatim Husain said at the
European Lung Cancer Conference.
He used ctDNA isolated from patients’ urine to test for the presence
of three different resistance mutations
within the epidermal growth factor receptor (EGFR) gene. Genetic testing of
biopsy specimens showed 10 patients
carried the T790M mutation, 18 carried
an exon 19 deletion, and eight carried
an exon 21 L858R mutation. Of these
36 mutations in 34 patients, testing
ctDNA isolated from urine identified
35 as positive, a 97% overall concordance rate.
In addition, testing with ctDNA from
urine also picked up three additional
T790M mutations not seen in the three
corresponding tumor-biopsy specimens,
but in patients with high clinical suspicion for carrying an EGFR mutation,
Dr. Husain reported.
Further evidence for the utility of
urinary ctDNA came from following
22 patients on treatment with erlotinib
(Tarceva) and monitored for their acquisition of an EGFR-gene mutation
making the tumor erlotinib resistant.
Dr. Husain and his associates ran a
DNA test every 3-6 weeks and tracked
the time until patients developed radiographic progression. Using urinary
ctDNA, they found four patients who
developed EGFR mutations 29-111 days
before clinical progression of the tumor
became radiographically apparent.
The ctDNA that ends up in a patient’s
urine starts out circulating in the blood;
urine works as the main elimination
route. Urine ctDNA is more concentrated than in blood, and ctDNA remains
stable in urine at ambient temperature
for 2 weeks, said Dr. Husain, an oncology researcher at the University of California San Diego, La Jolla.
“These interim results suggest that
use of urinary ctDNA has potential to
detect EGFR T790M status in a higher number of study subjects and may
make some patients eligible for therapy
who would by tissue biopsy be falsely
classified as negative,” Dr. Husain said
in a written statement. “Detecting the
emergence of EGFR T790M mutations
before progression has the potential to
enable physicians to better align therapeutic selection and inform early therapeutic decision making,” he said.
Testing ctDNA in patients’ urine is a
“novel way to do noninvasive testing,”
said Dr. Egbert F. Smit, professor of
pulmonary medicine at VU University
Medical Center in Amsterdam and the
meeting’s designated discussant for Dr.
Husain’s report. “It’s attractive for collecting ctDNA because you get a high
concentration, and it has potential for
a high level of sensitivity. It may have
potential for showing how a tumor reacts to treatment. The method seems
robust, but we still need data on reproducibility and cost effectiveness,” Dr.
Smit cautioned.
[email protected]
On Twitter @mitchelzoler
oncologyreport.com3
Rociletinib active against resistant NSCLC
BY MARY ANN MOON
R
FROM TH E NEW ENGLAND
JOURNAL OF MEDICINE
ociletinib, a third-generation
EGFR tyrosine kinase inhibitor
that targets mutations causing
treatment resistance, showed sustained
activity against resistant non–small cell
lung cancer (NSCLC) in a phase I clinical trial, according to a report published
online April 30 in the New England
Journal of Medicine.
The study, sponsored by Clovis Oncology, the maker of rociletinib, involved
130 patients enrolled over the course
of 2 years at 10 medical centers in the
United States, France, and Australia.
All the study participants had received
at least one first- or second-generation
EGFR inhibitor (usually erlotinib), and
their NSCLC tumors had mutated and
developed resistance to the therapy.
Half of these patients had three or
more sites of metastasis, and 44% had
brain involvement, said Dr. Lecia V.
Sequist of the deparment of medicine,
Massachusetts General Hospital, Boston, and her associates.
A total of 92 patients received therapeutic doses of rociletinib. After a median follow-up of 10 weeks, the response
rate among the 46 whose cancer had
known EGFR T790M mutations was
59%; 43 of these 46 patients achieved a
partial response, a complete response,
or disease stabilization. As expected,
the response rate was lower, at 29%,
among the 17 patients whose tumors
were T790M negative, the investigators
reported (New Engl. J. Med. 2015 April
30 [doi:10.1056/NEJMoa1413654]).
“Rociletinib did not cause the syndrome of rash, stomatitis, and paronychia that is associated with inhibition of
nonmutant EGFR,” they wrote, and the
most common grade 3 toxic effect was
hyperglycemia. No hyperglycemic events
led to discontinuation of treatment,
and most were managed with a dose
reduction plus use of an oral hypoglycemic agent, usually metformin. Both the
hyperglycemia and the metformin may
have contributed to gastrointestinal adverse events, which were generally mild.
The main limitation of this study is
the small number of patients who have
received rociletinib. Larger studies of
the agent are now underway, Dr. Sequist
and her associates said.
This study was funded by Clovis
Oncology, maker of rociletinib, which
also participated in study design and
data collection and analysis. Dr. Sequist
reported receiving personal fees from,
and consulting for, Clovis Oncology,
AstraZeneca, Boehringer Ingelheim,
Novartis, Genentech, Merrimack, and
Taiho, and her associates reported ties
to numerous industry sources.
VITALS
Key clinical point: Rociletinib
exerted prolonged disease
control in a phase I study of
resistant non–small cell lung
cancer.
Major finding: After a median
follow-up of 10 weeks, the
response rate among the 46
patients whose NSCLC had
known EGFR T790M mutations was 59%.
Data source: An international
phase I trial of rociletinib in
130 patients whose NSCLC
developed resistance to EGFR
tyrosine kinase inhibitors.
Disclosures: This study was
funded by Clovis Oncology,
maker of rociletinib, which
also participated in study design and data collection and
analysis. Dr. Sequist reported
receiving personal fees from,
and consulting for, Clovis
Oncology, AstraZeneca, Boehringer Ingelheim, Novartis,
Genentech, Merrimack, and
Taiho, and her associates reported ties to numerous industry sources.
[email protected]
LUNG CANCER
4
May 2015 • The Oncology Report
New agent targets EGFR resistance
in non–small cell lung cancer
VITALS
BY MARY ANN MOON
Key clinical point: AZD9291
was highly active against advanced NSCLC that had mutated to become resistant to
treatment with EGFR tyrosine
kinase inhibitors.
Major finding: The objective
response rate was 51% in the
entire study population and
61% in the subset of patients
with known EGFR T790M mutations.
Data source: An industry-funded phase I clinical trial of
253 patients in nine countries
whose advanced NSCLC had
developed treatment resistance.
Disclosures: This study was
funded by Astra Zeneca, maker of AZD9291. Dr. Janne
reported ties to AstraZeneca,
Boehringer Ingelheim, Chugai,
Pfizer, Merrimack, Clovis Oncology, Roche, and Gatekeeper, as well as several patents
related to genetically targeted
cancer treatments; his associates reported ties to numerous
industry sources.
A
FR O M TH E N E W E N G LA N D
JOURNAL OF MEDICINE
new agent targeting tumors that
develop resistance to EGFR tyrosine kinase inhibitors proved
to be “highly active” in a phase I clinical
trial involving 253 patients with advanced, resistant NSCLC, according to
a report published online April 30 in the
New England Journal of Medicine.
Most patients who initially respond to
EGFR tyrosine kinase inhibitors such as
gefitinib, erlotinib, and afatinib develop
resistance and show disease progression
within 2 years, because the tumors develop additional EGFR mutations, particularly T790M resistance mutations.
Preliminary studies suggested that a
new oral agent, AZD9291, would target
T790M-mediated resistance. In a phase
I trial to assess its safety and efficacy,
127 study participants had known EGFR
T790M mutations, and the remainder
had other or unknown mutations, said
Dr. Pasi A. Janne of the Lowe Center
for Thoracic Oncology and the Belfer
Institute for Applied Cancer Science,
Dana-Farber Institute, Boston, and his
associates.
The study – designed and funded by
AstraZeneca, which also collected and
analyzed the data in conjunction with
the scientific authors – was conducted at 33 sites in Japan, South Korea,
Taiwan, France, Spain, Germany, Australia, the United Kingdom, and the
United States. Of the 239 patients who
could be evaluated for a response, 123
(51%) showed a partial or complete
response. In the subset of patients with
known EGFR T790M mutations, the
objective response rate was even higher, at 61%.
In contrast, the objective response
rate was 21% in the subset of 61 patients who did not have known EGFR
T790M mutations, the investigators
said (N. Engl. J. Med. 2015 April 30
[doi:10.1056/NEJMoa1411817]).
Median progression-free survival was
estimated to be 9.6 months in patients
with EGFR T790M-positive tumors, although many are still alive and the final
survival data have yet to be calculated.
In contrast, progression-free survival
was 2.8 months in patients with EGFR
T790M-negative tumors.
No dose-limiting toxic effects occurred and therefore the maximal efficacy dose with an acceptable level of
adverse events cannot be established yet.
The most common adverse events were
diarrhea (47% of patients), rash (40%),
nausea (22%), and decreased appetite
(21%). Serious events that were considered to be possibly treatment-related
LUNG CANCER
VIEW ON THE NEWS
Cancers will continue to mutate
F
inding effective and relatively safe agents to address drug resistance in NSCLC is encouraging,
and there is every reason to be cautiously optimistic
about lung cancer treatment. But it is almost certain that cancer cells will continue to evolve and
eventually develop resistance to these agents also.
The keys to keeping up with evolving cancers are
to continue performing genomic analysis of resistant lesions and to translate laboratory findings to
the clinic as rapidly as possible.
Dr. Ramaswamy Govindan is with the Alvin J. Siteman
Cancer Center at Washington University, St. Louis.
He reported receiving consulting fees and honoraria
from Pfizer, Merck, Boehringer Ingelheim, Clovis Oncology, Helsinn Healthcare, Genentech, AbbVie, and
GlaxoSmithKline. Dr. Govindan made these remarks in
an editorial accompanying Dr. Janne’s report
(N. Engl. J. Med. 2015 April 30 [doi:10.1056/NEJMe1500181]).
oncologyreport.com5
occurred in 6% of patients, and included one fatal case of pneumonia and six
cases of pneumonitis-like events that resolved when the drug was discontinued.
These findings demonstrate that “a
structurally distinct EGFR inhibitor, one
that is selective for the mutated form
of EGFR, can be clinically effective and
has a side-effect profile that is not dose
limiting in the majority of patients in
whom T790M-mediated drug resistance
has developed,” Dr. Janne and his asso-
ciates said.
Astra Zeneca is the maker of
AZD9291. Dr. Janne reported ties to
AstraZeneca, Boehringer Ingelheim,
Chugai, Pfizer, Merrimack, Clovis Oncology, Roche, and Gatekeeper, as well
as several patents related to genetically
targeted cancer treatments; his associates reported ties to numerous industry
sources.
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6
May 2015 • The Oncology Report
Lung adenocarcinoma subtype predicts
benefit from adjunct chemotherapy
VITALS
LUNG CANCER
Key clinical point: Invasive adenocarcinomas with micropapillary (MIP) and predominantly
solid (SOL) patterns had greater benefit from adjuvant chemotherapy than acinar (ACN)
and papillary (PAP) subtypes.
Major finding: Grouped by subtype, patients in the MIP/SOL
group had poorer disease-free
survival (DFS) and specific disease-free survival (SDFS) than
the ACN/PAP group (P < .01).
The MIP/SOL group derived
significant benefit in DFS
(P < .001) and SDFS (P < .001),
but not OS, from adjuvant
chemotherapy.
Data source: Histology data was
analyzed from 575 patients
with lung adenocarcinomas
who participated in adjuvant
chemotherapy clinical trials
and were part of the Lung
Adjuvant Cisplatin Evaluation
Biomarker (LACE-Bio) collaborative group.
Disclosures: Dr. Tsao reported
having no disclosures. Many of
his coauthors reported ties to
several industry sources.
BY JENNIFER KELLY SHEPPHIRD
FROM J O U R N A L O F C LI N I C A L O N C O LO G Y
A
nalysis of a large cohort of patient tumor samples from four
international adjuvant chemotherapy trials confirms the prognostic
value of the latest, soon-to-be-published, World Health Organization lung
adenocarcinoma classifications, investigators reported online April 27 in the
Journal of Clinical Oncology.
More than half of all patients with
early-stage non–small cell lung cancer
will have recurrence after primary surgery and “identifying prognostic factors
beyond stage is crucial to select patients
who need adjuvant therapies. … The
results of our study represent the first
markers, to our knowledge, from the
LACE-Bio [the Lung Adjuvant Cisplatin Evaluation Biomarker] project that
suggest a significant predictive value for
survival benefit from ACT [adjuvant chemotherapy] in patients with early-stage
lung adenocarcinoma,” Dr. Ming-Sound
Tsao with the Princess Margaret Cancer
Centre, University of Toronto, and his
colleagues wrote (J. Clin. Oncol. 2015
Apr. 27 [doi:10.1200/JCO.2014.58.8335]).
A new lung adenocarcinoma classification system based on the predominant histological pattern observed
in resected tumors, including lepidic
(LEP), papillary (PAP), acinar (ACN),
micropapillary (MIP), and predominantly solid (SOL) subgroups, forms the
basis for the fourth edition of the WHO
classification to be published in 2015.
The LACE-Bio collaborative group
evaluated biomarkers using data from a
large cohort of patients participating in
four ACT trials: the IALT (International
Adjuvant Lung Cancer Trial), ANITA
(Adjuvant Navelbine International Trialist Association), JBR-10, and CALGB
(Cancer and Leukemia Group B; now
Alliance for Clinical Trials in Oncology).
The current study evaluated the
prognostic value of the classification
regarding survival from adjuvant che-
motherapy using hematoxylin and eosin
(HE)-stained slides from a subset of
these patients. Because of the low numbers of representative samples in some
groups, the five subtypes were collapsed
into three groups: LEP, ACN/PAP, and
MIP/SOL.
Patients with invasive lung adenocarcinoma with MIP and SOL patterns had
poorer disease-free survival (DFS) and
specific disease-free survival (SDFS) compared with the ACN/PAP subtypes. Furthermore, in early-stage adenocarcinoma,
MIP/SOL-predominant histology predicted benefit from ACT in DFS and SDFS.
Multivariate analysis showed a marginally significant chemotherapy benefit
in OS for MIP/SOL (hazard ratio, 0.71;
95% confidence interval, 0.51-0.99; P =
.04) but not for ACN/PAP. There was a
significant ACT benefit within the MIP/
SOL group for DFS and SDFS (P < .001
for both), but not within the ACN/PAP
group.
At a median follow-up of 5.6 years,
among 575 patients, there were 269
(47%) events for OS, 320 (56%) for DFS,
and 292 (51%) for SDFS. The primary endpoint was OS, and secondary
endpoints were DFS, defined as time
from random assignment to first event
(recurrence or death) and specific DFS
defined as time to first cancer-related
event. The prognostic impact of adenocarcinoma subtype on ACT benefit was
determined by comparison with 293
patients in the observation arm who did
not receive ACT.
Several previous studies demonstrated
that patients with lung adenocarcinoma with predominantly MIP and SOL
patterns had the worst outcomes. The
association of the MIP growth pattern
and poor outcomes in breast cancer is
well known. The SOL pattern describes
poorly differentiated carcinomas, and
higher rates of this subtype have been
observed in studies that included patients with higher stage disease.
[email protected]
oncologyreport.com7
ELCC: NSCLC mutation testing highlights
ctDNA’s limitations
VITALS
BY MITCHEL L. ZOLER
AT ELCC 2015
Frontline Medical N ews
GENEVA – The tests widely available
today that use a cancer patient’s tumor
DNA that circulates in the blood to
detect a treatment-altering lung cancer
mutation vary widely in sensitivity,
meaning that using circulating DNA to
identify a clinically important mutation
should be limited to when biopsying
the primary does not yield enough
DNA for testing.
“It is important to use robust and sensitive methods” when trying to match
treatment to the molecular specificities
of each patient’s tumor, Dr. Martin
Reck said at the European Lung Cancer
Conference.
Results from a study that prospectively compared DNA analysis for mutations in the epidermal growth factor
receptor (EGFR) gene in tumor biopsies
from 1,162 patients with advanced non–
small cell lung cancer with DNA analysis of circulating tumor DNA
(ctDNA) from the same patients showed
that ctDNA analysis had 46% sensitivity,
compared with tumor biopsy DNA, reported Dr. Reck, a thoracic oncologist
at the Lung Clinic in Grosshandsdorf,
Germany. This high level of false-negative results with ctDNA analysis
produced a positive predictive value
Dr. Egbert F. Smit
of 78%. In contrast, ctDNA has a specificity of 97% and a negative predictive
value of 90%.
The results from the international
study, which included 881 patients from
seven European countries plus 281
patients from Japan, highlighted the
divergent concordance among EGFR
mutation comparisons of ctDNA and
biopsy DNA depending on which DNA
tests were used. Participating physicians
could order whichever genetic analyses
they wanted. A subanalysis of the study
showed, for example, that among the
138 patients whose tumor and ctDNAs
were both evaluated for EGFR mutations using the therascreen test marketed by QIAGEN the concordance rose to
95%, the sensitivity of ctDNA was 73%,
and the positive predictive value was
94%, Dr. Reck reported.
The Europe-Japan Diagnostic Study
for EGFR Testing (ASSESS) enrolled
patients with either newly diagnosed,
locally advanced stage IIIA or IIIB metastatic non–small cell lung cancer or
patients with recurrent non–small cell
lung cancer following surgical resection.
Patients averaged about 67 years old,
and about 85% had stage IV disease.
The genetic analyses identified EGFR
mutations in 31% of the Japanese patients and in 12% of those in Europe.
[email protected]
On Twitter @mitchelzoler
LUNG CANCER
F rontline Medical N ews
Dr. Martin Reck
Key clinical point: In a real-world setting genetic tests
that used ctDNA to find treatment-determining mutations
in patients with advanced lung
cancer were generally less
sensitive than genetic tests
using biopsy material from the
primary tumor.
Major finding: Mutation assessment results from ctDNA and
biopsy DNA showed concordance in 89% of specimen
pairs tested.
Data source: Prospective study
with paired test results from
1,162 patients treated in seven European countries or in
Japan.
Disclosures: The ASSESS study
was funded by AstraZeneca.
Dr. Reck has been a speaker
and consultant to AstraZeneca
and seven other companies.
8
May 2015 • The Oncology Report
VIEW ON THE NEWS
Use ctDNA with caution
T
he ASSESS study is the largest evaluation of
using ctDNA to test the status of a lung tumor
for the presence of a mutation in the gene for the
epidermal growth factor receptor. It also gives us
insight into the feasibility and effectiveness of using
this approach in routine practice, outside of a rigorously designed trial. The result was that mutation
testing using plasma specimens to obtain circulating
tumor DNA was generally doable but resulted in
low sensitivity and a low positive predictive value.
The low sensitivity seen overall in ASSESS likely resulted from the multiple testing reagents,
commercially available testing kits, and in-house
techniques used by individual laboratories in this
international study done in diverse settings. Some
of the tests for epidermal growth factor receptor
(EGFR) mutations are quite sensitive, and others
less so. The specific testing method used matters
quite a lot. The heterogeneity of methods used in
ASSESS reflects the diversity of what usually happens in real-world practice.
Based on the sensitivity limitations, I currently
see using ctDNA to test for EGFR mutations only
when this is the only option for mutation assessment because a conventional biopsy of the primary
tumor failed to provide enough DNA for EGFR
mutation testing. Although it is hard to find specific
numbers on how often this situation arises in cur-
rent practice, it seems to happen roughly 10%-30%
of the time. So, for about one-fifth of patients with
newly diagnosed or recurrent stage III or IV lung
cancer EGFR mutation assessment using ctDNA
will be necessary.
The data from ASSESS and other studies show
that when ctDNA testing identifies an EGFR mutation you can rely on its accuracy. The problem is
when ctDNA testing fails to identify an EGFR mutation. In those situations you need to be cautious
as you can’t rely on a negative result as being a
true negative. I would also be cautious about using
ctDNA testing to follow lung cancer patients, as the
clinical importance of finding new EGFR alleles
appearing in the patient’s blood over time is not
yet clear. We need more studies that follow these
patients and changes in their EGFR ctDNA over
time to determine the clinical relevance of these
changes.
The results from ASSESS add to the existing body
of evidence that ctDNA testing to find EGFR mutations is feasible in a real-world setting.
Dr. Egbert F. Smit is a professor of pulmonary medicine
at the VU University Medical Center in Amsterdam. He
had no relevant disclosures. He made these comments
in an interview and as the designated discussant for the
ASSESS study at the meeting.
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oncologyreport.com9
VIDEO SPOTLIGHT
F rontline M edical N ews
Circulating tumor DNA testing shows real-world limits
Circulating tumor DNA currently has one role to play in routine management of lung cancer patients: To check at
the time of diagnosis for a treatment-defining mutation in the tumor’s epidermal growth factor receptor gene, but
only when the DNA available from the tumor biopsy is inadequate for analysis, Dr. Egbert F. Smith said in a video
interview at the European Lung Cancer Congress. That happens for about 10%-25% of newly diagnosed lungcancer patients, he said.
Dr. Smit, the designated discussant for the Europe-Japan Diagnostic Study for EGFR [epidermal growth factor
receptor] Testing (ASSESS) – a study that ran mutational analysis of the EGFR genes in 1,162 patients using
circulating tumor (ct) DNA – highlighted the main limitation of this method in the routine-practice setting used
by ASSESS: The test’s low sensitivity of 46%.
He attributed this in part to the wide range of methods used to perform the ctDNA analyses in the international
study. “Some methods are sensitive, and some are not so sensitive,” said Dr. Smit, professor of pulmonary
medicine at VU University Medical Center, Amsterdam.
“You have to think about the limits of your [ctDNA] test, and the analytical sensitivity of the laboratory,” he said.
These factors can make a ctDNA test unreliable for ruling out an EGFR mutation. “Do not think that patients do
not have an EGFR mutation based only on their plasma circulating DNA,” Dr. Smit advised.
VIEW VIDEO ONLINE uu
LUNG CANCER
10
May 2015 • The Oncology Report
TKI benefit greater with certain EGFR
mutations in NSCLC tumors
VITALS
LUNG CANCER
Key clinical point: Risk of non–
small cell lung cancer (NSCLC) progression is reduced
by 63% for patients with epidermal growth factor receptor
(EGFR) mutations who take
tyrosine kinase inhibitors over
chemotherapy, and the reduction is 50% greater for exon
19 deletions compared with
exon 21 leucine to arginine
substitutions.
Major finding: Patients with
exon 19 deletions had prolonged PFS compared with
exon 21 L858R substitutions:
hazard ratios were 0.24 (95%
CI, 0.20-0.29) and 0.48
(0.39-0.58), respectively (Pinteraction < .001).
Data source: A meta-analysis
of seven trials that compared
EGFR tyrosine kinase inhibitors with chemotherapy in a
total of 1,649 patients with
NSCLC and EGFR mutations.
Disclosures: Dr. Chee Khoon
Lee reported receiving funding
from GlaxoSmithKline and
Boehringer Ingelheim. Many of
his coauthors reported ties to
several industry sources.
BY JENNIFER KELLY SHEPPHIRD
FROM J O U R N A L O F C LI N I C A L O N C O LO G Y
R
isk of non–small cell lung cancer progression is reduced by
63% for patients with epidermal
growth factor receptor mutations who
take tyrosine kinase inhibitors over
chemotherapy, and the benefit is 50%
greater for those with exon 19 deletions
compared with exon 21 leucine to arginine substitutions, according to a meta-analysis published online April 20 in
the Journal of Clinical Oncology.
More than 90% of epidermal growth
factor receptor (EGFR) mutations in
tumors of non–small cell lung cancer
(NSCLC) patients are so-called common
mutations of exon 19 deletion or exon
21 L858R substitution, and while both
mutations are recognized as predicting
benefit with EGFR TKIs, this meta-analysis of seven studies of NSCLC patients
with the mutations (56% exon 19 deletions and 44% L858R), showed 50%
greater relative benefit in progression
free survival (PFS) for patients with
exon 19 deletions relative to L858R (HR,
0.24; 95% CI, 0.20-0.29 vs. 0.48; 0.390.58).
“These findings have important implications for clinical trial design and interpretation, economic analysis, and future
drug development for EGFR-mutated,
advanced NSCLC,” wrote Dr. Chee
Khoon Lee of the National Health and
Medical Research Council Clinical Trials
Centre, University of Sydney, Australia,
and associates ( J. Clin. Oncol. 2015 April
20 [doi: 10.1200/JCO.2014.58.1736]).
The researchers also found a 36%
greater PFS benefit for never-smokers
compared with current or former smokers. The pooled HR for PFS among the
70% of patients who never smoked was
0.32 (0.27-0.37) compared with 0.50
(0.40-0.63) for the 30% who currently or
formerly smoked (Pinteraction = .002).
Women had a 27% greater PFS benefit than did men, a difference previously
thought due to the higher EGFR mutation rate in women or due to lower
smoking rates in women than men. All
patients in the current study had EGFR
mutations, and the sex-based difference
in PFS benefit was still apparent. Multivariate analysis showed also that the
benefit was independent of smoking
status.
Regarding associations between
EGFR mutation type and clinical characteristics, no significant correlations
were observed between mutation type
and age, performance status, sex, histology, or smoking.
In patients treated with TKIs, exon 19
deletions were associated with longer
PFS than L858R (median PFS 11.8 vs.
10.0 months; P = .006). By contrast,
among those randomly assigned to
chemotherapy, L858R mutations were
associated with longer PFS (6.1 vs. 5.1
months; P = .003).
The report was limited by the absence
of overall survival data, which the researchers said they plan to include in an
upcoming analysis when the data become available.
[email protected]
oncologyreport.com11
Advanced NSCLC responds
to nivolumab
BY JENNIFER KELLY SHEPPHIRD
FROM JOURNAL OF CLINICAL ONCOLOGY
T
VITALS
Key clinical point: Nivolumab
monotherapy for advanced,
heavily pretreated non–small
cell lung cancer (NSCLC)
generated outcomes that
surpassed expectations for
second- and third-line chemotherapies.
Major finding: At 3 mg/kg,
ORR was 24%, OS was 14.9
months, and 1-, 2-, and 3-year
survival rates were 56%, 45%,
and 27%, respectively.
Data source: The phase I multicenter dose escalation trial
evaluated nivolumab at 1, 3,
and 10 mg/kg in 129 patients,
54% of whom had received at
least three prior treatments.
Disclosures: Dr. Gettinger
reported receiving research
funding from or having consulting or advisory roles with
Bristol-Myers Squibb, ARIAD
Pharmaceuticals, Genentech,
AstraZeneca, Bayer Pharmaceuticals, and Pfizer. Many of
his coauthors reported ties to
several industry sources.
[email protected]
LUNG CANCER
he immune checkpoint inhibitor
nivolumab generated encouraging response rates and overall
survival rates in heavily pretreated patients with non–small cell lung cancer,
according to a report published online
April 20 in the Journal of Clinical Oncology.
In a phase I multicenter dose escalation trial evaluating nivolumab at 1, 3,
and 10 mg/kg in 129 patients, the overall response rate (ORR) across all doses
was 17.1% (95% CI, 11.0% to 24.7%),
duration of response was 17.0 months
(1.4+ to 36.8+), overall survival (OS)
was 9.9 months (7.8 to 12.4), and 1-,
2-, and 3-year survival rates were 42%,
24%, and 18%, respectively.
At 3 mg/kg, the dose currently being
used for phase III trials, ORR was 24.3%
(11.8% to 41.2%), OS was 14.9 months
(7.3 to 30.3), and 1-, 2-, and 3-year survival was 56%, 42%, and 27%, respectively.
The ORR in the subgroup of patients
who had received three or more prior
treatments was 21%, similar to the ORR
for the entire population, reported Dr.
Scott N. Gettinger of the Yale Cancer
Center, New Haven, Conn., and associates ( J. Clin. Oncol. 2015 April 20
[doi:10.1200/JCO.2014.58.3708]).
“This differs from chemotherapy,
where response rates decrease with
subsequent lines of therapy. [Outcomes
with nivolumab treatment] surpass
expectations of second- and third-line
chemotherapies, taking into account
the caveats of a phase I dose-escalation/
expansion trial design,” the researchers
wrote.
Expectations for current second-line
chemotherapies for advanced non–small
cell lung cancer (NSCLC) are ORRs
of 7% to 9%, median OS of about 8
months, and 1-year survival of about
30%.
Treatment-related adverse events
of any grade occurred in 71% of patients, most commonly fatigue (24%),
decreased appetite (12%), and diarrhea
(10%). Grade 3-4 events occurred in 14%
of patients, most commonly fatigue
(3%). There were three treatment-related deaths, all due to pneumonitis. No
clear relationship between pneumonitis
occurrence and dose level or treatment
duration was observed. Guidelines for
early identification and management of
pneumonitis are now in place.
Additional phase I, II, and III trials are
underway to evaluate nivolumab as well
as other therapeutic antibodies directed
to the immune checkpoint receptor,
programmed death 1 (PD-1), or its ligand (PD-L1). The trials have produced
consistently encouraging results in patients with advanced NSCLC.
“Efforts are now focusing on evaluating potential predictive biomarkers,
such as tumor expression of PD-L1, to
select populations most likely to benefit from antibodies targeting the PD-1
axis,” wrote Dr. Gettinger and his associates.
12
May 2015 • The Oncology Report
AACR: KEYNOTE-001 takes step toward
PD-L1 blocker biomarker of response
VITALS
LUNG CANCER
Key clinical point: Pembrolizumab provided durable
responses in NSCLC, with clinical outcomes correlating with
a proposed biomarker.
Major finding: Objective response rates were 42.5% in
patients with ≥ 50% PD-L1 tumor expression vs. 16.5% and
10.7% for patients with 1%49% and < 1% PD-L1 tumor
expression.
Data source: Phase I study in
495 patients with advanced or
metastatic non–small cell lung
cancer.
Disclosures: The study was
funded by Merck. Dr. Caron’s
institution received funds
to conduct the trial, but he
declared no other conflicts of
interest. Dr. Topalian reported
serving on a program committee or speaking for Bristol-Myers Squibb, Five Prime
Therapeutics, GlaxoSmithKline, Jounce Therapeutics,
and MedImmune.
DR. EDWARD GARON
BY PATRICE WENDLING
FR O M TH E A A C R A N N U A L M E E TI N G
R
esults from KEYNOTE-001 show
that not only is the anti-PD-L1
antibody pembrolizumab clinically active in advanced non–small cell
lung cancer, but that PD-L1 expression
is a marker of response, as well.
The objective response rate was
45.2% for patients with programmed
cell death ligand 1 (PD-L1) expression in
at least half of their tumor cells, including 44% in previously treated patients
and 50% in treatment-naive patients.
For patients with 1% to 49% and
< 1% tumor PD-L1 expression, objective response rates were 16.5% and
10.7%, respectively, Dr. Edward Garon
of the University of California, Los Angeles, reported at the annual meeting
of the American Association for Cancer
Research.
About a quarter of those screened
had PD-L1 expression in at least half of
their tumor cells.
Median progression-free survival
(PFS) in this subgroup was 6.3 months
vs. 3.3 months in patients with 1%-49%
tumor PD-L1 and 2.3 months in those
with < 1% PD-L1.
After a median follow-up of 10.9
months, median overall survival was
not reached in patients with at least
50% tumor PD-L1 expression and was
8.8 months in both groups with lesser
degrees of tumor PD-L1 expression,
according to results simultaneously reported in the New England Journal of
Medicine (2015 April 19 [doi:10.1056/
NEJMoa1501824]).
“I think that with [these] data, we
can now confidently say that in previously treated patients who have PD-L1
expression in at least half of their cells,
pembrolizumab is associated with superior clinical outcomes, clearly, than what
would be anticipated with cytotoxic
chemotherapy,” Dr. Garon said during a
press briefing.
Outcomes in patients with lesser
tumor PD-L1 expression may also be
better than what is seen with comparators, but complete data on that will
require data from randomized studies,
he added.
Press briefing moderator Dr. Suzanne
Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer
Center in Baltimore, pointed out that
more than three-fourths of patients in
the study had progressed on prior systemic therapies.
“This is a very difficult-to-treat patient
population where the impact of secondand third-line agents is generally not
expected to prolong survival,” she said.
“These results are especially impressive
I think in this particular treatment setting.”
Results from KEYNOTE-001 were
drawn from 495 patients with advanced
or metastatic non–small cell lung cancer, including 182 patients assigned to
a training group in which the PD-L1
cutoff value was selected and 313 patients with measurable disease assigned
to an independent biomarker validation
group. PD-L1 status was assessed in
tumor samples by a prototype immunohistochemistry assay using the 22C3
antibody clone (Merck). Patients were
randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3
weeks or 10 mg/kg every 2 weeks.
In the training group, 171 patients
were previously treated and 11 were
treatment naive, with 129 remaining after exclusions for cutoff selection. In the
validation group, 223 patients were previously treated and 90 were treatment
naive, with 204 biomarker evaluable patients remaining after exclusions.
The objective response rate among
the entire 495 patients was 19.4%,
including 18% in previously treated
patients and 24.8% in treatment-naive
patients, Dr. Garon said.
Median PFS was 3.7 months, 3.0
months, and 6.0 months and median
overall survival 12 months, 9.3 months,
and 16.2 months, respectively.
oncologyreport.com13
There were no clear differences in
efficacy and safety between dosing regimens, he said.
Treatment-related adverse events occurred in 351 patients (71%), the most
common being fatigue, pruritus, and
decreased appetite. Grade 3 or higher
events were reported in 47 patients
(9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.
Based on the current data, Dr. Topalian asked how the proposed PD-L1
biomarker would be used in clinical
practice. She noted that the situation
is more clearcut with the kinase inhibitor class of drugs in which the biology
tells us whether the drug is unlikely to
work based on whether the patient has
a particular mutation, like the BRAFV600E
mutation in melanoma.
“This kind of biomarker is a lot more
blurry and you saw that even patients
with lower levels of expression of this
marker still have notable response
rates,” Dr. Topalian said.
Dr. Garon responded that there are
two important aspects to a biomarker.
“One is that when you select patients
who are positive, you do a very good
job of enriching for patients with good
clinical outcome, and this data set I believe very well addresses that piece,” he
said. “The other piece, which is a shortfall and in some respects a fortunate
shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like
with this biomarker of demonstrating
the group of people who is not likely to
benefit.”
DR. SUZANNE TOPALIAN
[email protected]
On Twitter @pwendl
VIDEO SPOTLIGHT
It’s time for oncologists to
radically expand their use of
adjuvant treatment with a
tyrosine-kinase inhibitor in
patients with stage IB-III non–
small cell lung cancer that has
a suitable mutation who have
undergone surgical resection and
received adjuvant chemotherapy
along with, when appropriate,
adjuvant radiation therapy, Dr.
Mark G. Kris said in a video
interview at the European Lung
Cancer Congress.
Giving such patients prolonged
treatment with a tyrosinekinase inhibitor when their
tumor carries a mutation in the
epidermal growth factor receptor
gene boosts their chance
for complete cure, increases
survival, and should be much
more widely used than it’s
been up until now, said Dr. Kris
of Memorial Sloan Kettering
Cancer Center, New York.
[email protected]
On Twitter @mitchelzoler
VIEW VIDEO ONLINE uu
LUNG CANCER
F rontline Medical N ews
TKIs merit broader use as NSCLC adjuvant
14
May 2015 • The Oncology Report
New light shed on olaparib therapy
in ovarian cancer
BY SUSAN LONDON
AT THE A N N U A L ME E TI N G O N WO ME N ’ S C A N C E R
DR. URSULA A. MATULONIS
GYNECOLOGIC MALIGNANCIES
“
Olaparib
treatment
benefits were
observed in
all the patient
subgroups. The
safety profile
of olaparib was
acceptable in
patients who
had received
three or more
prior lines of
therapy.
CHICAGO – Olaparib improves outcomes in women with ovarian cancer
who have a germline BRCA mutation,
but its use at least as maintenance
therapy is not cost-effective, according to research reported at the annual
meeting of the Society of Gynecologic
Oncology.
The Food and Drug Administration
approved olaparib, an oral inhibitor of
poly-ADP-ribose polymerase (PARP),
in December 2014 for the treatment
of patients who have recurrent ovarian
cancer with a germline BRCA mutation
and have received at least three prior
lines of therapy. It is currently not approved for maintenance therapy in the
United States.
Subsequent therapy may
mask a survival benefit
In the first of three studies, investigators led by Dr. Ursula A. Matulonis
performed a post hoc, exploratory
analysis of data from a pivotal randomized phase II trial in platinum-sensitive
relapsed ovarian cancer (Study 19). The
trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo
as maintenance therapy.
A previous stratified analysis among
265 patients revealed that those with
a BRCA mutation had a marked progression-free survival benefit with
olaparib versus placebo (11.2 vs. 4.3
months; hazard ratio, 0.18) but no
significant gain in overall survival
(34.9 vs. 31.9 months; hazard ratio,
0.73) (Lancet Oncol. 2014;15:852-61),
according to Dr. Matulonis, medical director and program leader of
the medical gynecologic oncology
program at the Dana-Farber Cancer
Institute and an associate professor of
medicine at Harvard Medical School,
both in Boston.
Crossover to olaparib was not permitted in the trial, but patients may have
accessed PARP inhibitors outside of the
study, she noted. “It was hypothesized
that patients switching treatments may
have reduced the beneficial impact of
olaparib on the overall survival results.
We know that switching is common in
randomized trials in oncology but difficult to prevent practically and ethically,
and it certainly may make an impact on
overall survival.”
In the new, exploratory analysis, she
and her colleagues reassessed outcomes
after excluding all trial sites at which at
least one patient received a PARP inhibitor after progression, which left 198
patients.
Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA
mutation (12.4 vs. 4.4 months; hazard
ratio, 0.14). But now, olaparib also
conferred a significant overall survival
benefit, halving the risk of death (34.9
vs. 26.6 months; hazard ratio, 0.52),
reported Dr. Matulonis, who disclosed
that she has received research funding
and speakers bureau remuneration from
AstraZeneca.
“This change in overall survival hazard ratio may suggest a confounding
influence that reduced the beneficial
impact of olaparib,” she said. “There
remains a degree of uncertainty owing
to small sample sizes and lack of data
maturity, so further analysis on more
mature data is required to confirm these
findings.”
Analysis confirms efficacy, safety
in heavily pretreated patients
In the second study, Dr. Matulonis and
colleagues performed a pooled analysis to assess the impact of olaparib in
patients with advanced relapsed ovarian cancer having a germline BRCA
mutation. Results were based on 273
patients given olaparib monotherapy in
six AstraZeneca-sponsored phase I and
II trials.
In the entire cohort, the overall response rate was 36% and the median
oncologyreport.com15
Therefore, the field should address
some key unanswered questions about
PARP inhibitor therapy, according to Dr.
Swisher: “Really, what is the best time
point for using it – is it at maintenance,
or is it at the time of relapse? And if we
use it as maintenance, is it in the primary setting or the recurrent setting?” she
elaborated.
She noted that women with somatic
BRCA mutations as opposed to germline ones seem to benefit similarly from
olaparib, but as insurance companies in
the United States often resist covering
tumor testing, this subset of women is
often missed. “Predictors of response
and resistance other than BRCA mutations are needed,” she added.
Models suggest maintenance
therapy is not cost-effective
In the third study, investigators led by
Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University
of Alabama, Birmingham, constructed
models to assess the cost-effectiveness
of olaparib maintenance therapy in patients with platinum-sensitive recurrent
ovarian cancer.
They used as a target population
5,549 women who had a complete
response to primary therapy, experienced a recurrence, and then had at
least a partial response to second-line
chemotherapy. Analyses assumed a
germline BRCA mutation prevalence
of 20%.
In the model, patients received six
cycles of chemotherapy, followed by
either observation or olaparib maintenance therapy. The cost of olaparib
was set at $7,000 per month, while the
cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse
events was not included in the model
as the majority of these in the phase
II trial were grade 1 or 2,” Dr. Smith
noted.
Results of the base case analysis
showed that among patients with
a BRCA mutation, the incremental
cost-effectiveness ratio (ICER) for
olaparib relative to observation was
$135,672 per progression-free life-year
saved – more than double the $50,000
threshold the investigators considered
DR. HALLER J. SMITH
Analyses
assumed a
germline BRCA
mutation
prevalence of
20%
.
GYNECOLOGIC MALIGNANCIES
duration of response was 7.4 months.
The corresponding values were 31%
and 7.8 months in the three-fourths of
patients who had received at least three
prior lines of chemotherapy.
Benefit was seen whether patients’
disease was platinum sensitive, resistant,
or unknown, Dr. Matulonis reported.
However, the response rate fell as the
number of previous lines of therapy
increased.
The rate of grade 3 or worse adverse
events was 50% in the total population
and 54% in the subset who received
three or more previous therapies,
and the rate of serious adverse events
was 30% and 34%, respectively. Eight
patients (all in the heavily pretreated
group) had a serious adverse event leading to death, but none were considered
causally related to olaparib.
“Olaparib treatment benefits were observed in all the patient subgroups,” Dr.
Matulonis said. “The safety profile of
olaparib was acceptable in patients who
had received three or more prior lines
of therapy.”
She noted that an ongoing series of
phase III trials of monotherapy in patients with germline BRCA mutations
– the Studies of Olaparib in Ovarian
Cancer (SOLO) 1, 2, and 3 trials –
should provide more information on
use of the drug in various settings.
Invited discussant Dr. Elizabeth
Swisher, medical director of the breast
and ovarian cancer prevention program
at the Seattle Cancer Care Alliance and
professor in the gynecologic oncology
division at the University of Washington, noted the uncertainty surrounding
the optimal use of PARP inhibitors
in ovarian cancer and mentioned that
olaparib is approved as maintenance
therapy in Europe.
“Many of you have probably been in
the same situation that I have, where I
have a patient in front of me and have
to say, ‘Yes, this would be a good drug
for you, but you need to fail a couple
more lines of chemotherapy first,’ ” she
said. “And we all know that later in the
disease course, GI symptoms become
more prominent and an oral drug may
not be tolerated, so we might lose the
opportunity to treat these patients with
these drugs.”
16
DR. ELIZABETH SWISHER
May 2015 • The Oncology Report
to be cost-effective, Dr. Smith reported. Among patients with wild type for
BRCA, the ICER was sharply higher, at
$315,840.
Sensitivity analyses showed that
olaparib therapy was still not cost-effective when the prevalence of BRCA
mutations and progression-free survival were varied. But the ICER fell to
$97,404 when the cost of the drug was
reduced to $5,000 and fell to $49,584
when it was reduced to $2,500.
“In order to achieve an ICER of less
than $50,000, the cost of olaparib would
have to be $2,500 or less per month,”
Dr. Smith said. However, “in the era of
molecular targeted therapies, an ICER
of less than $100,000 would be considered by many to be cost-effective,” she
acknowledged.
“While PARP inhibitors and other
molecular targeted therapies represent
exciting new therapeutic options for our
patients, the costs associated with these
drugs remain a significant concern. As
health care costs continue to increase,
cost-effectiveness studies are likely to
become a more important part of the
drug development and approval process,” she concluded.
[email protected]
Circulating tumor cells prognostic in
advanced cervical cancer
GYNECOLOGIC MALIGNANCIES
VITALS
Key clinical point: CTCs provide
prognostic information in women being treated for advanced
cervical cancer.
Major finding: Risk of death for
patients given cisplatin-paclitaxel plus bevacizumab was
reduced by 10% for those
who had a high pretreatment
level of CTCs and by 13% for
those who had a greater treatment-related decline in CTCs.
Data source: Analysis of 174
women with advanced cervical
cancer given chemotherapy
with or without bevacizumab
in a phase III trial.
Disclosures: Dr. Tewari disclosed that he is a consultant to Genentech/Roche,
Advaxis, and Caris Life Sciences; receives honoraria/
reimbursement or grants from
Genentech/Roche; and performs research for Caris Life
Sciences.
BY SUSAN LONDON
AT THE A N N U A L ME E TI N G O N WO ME N ’ S C A N C E R
CHICAGO – Circulating tumor cells
are a prognostic biomarker for overall
survival in women with advanced cervical cancer who are receiving chemotherapy with or without bevacizumab,
according to an analysis of the Gynecologic Oncology Group’s 240 trial.
The risk of death among patients given cisplatin-paclitaxel plus bevacizumab
was reduced by 10% for those who had
a higher pretreatment level of circulating tumor cells (CTCs) and by 13% for
those who had a greater treatment-related decline in CTCs, Dr. Krishnansu S.
Tewari reported at the annual meeting
of the Society of Gynecologic Oncology.
“We can predict that leaky vasculature
resulting from tumor angiogenesis may
permit systemic distribution of CTCs
through intratumoral vascular shunting,
and the vulnerability to anti-angiogenesis therapies may be due to this increased vascularization,” said Dr. Tewari
of UC Irvine Health in Orange, Calif.
In comments provided by e-mail,
session comoderator Dr. Charles N.
Landen Jr. of the University of Virginia,
Charlottesville, said that the study is
important in that it demonstrates the
feasibility of using CTCs as a biomarker in this setting, but its results are not
practice changing.
“If you had a decrease in CTCs, you
were more likely to have a good response to therapy. However, this was
not any better at detecting response
than conventional methods such as a
CT scan,” he explained.
Giving some background to the research, Dr. Tewari said that “it’s difficult
to monitor response in patients with advanced cervical cancer. Doing imaging
studies after every two cycles is expensive, and there are no validated serum
tumor markers in this disease. In addition, tumor is not often accessible for
interrogation to help guide subsequent
therapy when patients ultimately progress on anti-VEGF [vascular endothelial
growth factor] therapy. Finally, predictive biomarkers are lacking in advanced
cervical cancer.”
“CTCs can be seen as minimally invasive liquid biopsies, and their presence
in breast cancer, prostate cancer, and
non–small cell lung cancer has been correlated with survival,” he noted. “However, all three of those solid tumors
oncologyreport.com17
are known to spread hematogenously.
While hematogenous spread can occur
in cervical cancer, it is felt to be rare.”
The phase III trial enrolled women
with recurrent, persistent, or metastatic
cervical cancer and tested the addition
of bevacizumab (Avastin, manufactured by Genentech/Roche) to doublet
chemotherapy (cisplatin-paclitaxel or
topotecan-paclitaxel) given on 21-day
cycles. Main results showed a significant
gain in overall survival from the addition of bevacizumab (N. Engl. J. Med.
2014;370:734-43), leading to regulatory
approval of combination therapy in the
United States and elsewhere.
The new analysis focused on the 174
women (39%) in the trial who had 8.5
mL of whole blood collected for CTC
measurement before starting the first
cycle of therapy and, in most cases,
again 36 days after the first cycle.
The investigators were able to identify CTCs for 97% of patients in the
pretreatment sample and for 81% in
the post-treatment sample, Dr. Tewari
noted.
Results showed that the median CTC
count in the sample fell from seven cells
pretreatment to four cells post-treatment (P < .0001). Of note, there was no
correlation with the response to treat-
ment according to RECIST (Response
Evaluation Criteria in Solid Tumors).
Patients with high (above-median)
pretreatment levels of CTCs had significantly better median progression-free
survival with bevacizumab than without
it (10.8 vs. 6.9 months; hazard ratio
[HR], 0.59). In contrast, there was no
significant benefit for patients with low
(below-median) pretreatment levels of
CTCs (7.3 and 6.2 months).
Among patients given cisplatin-paclitaxel plus bevacizumab, the higher
the pretreatment CTC level, the lower
the risk of death (HR, 0.90). Among
patients given cisplatin-paclitaxel overall, the higher the post-treatment CTC
level, the greater the risk of death (HR,
1.12), Dr. Tewari reported.
Finally, the greater the decline in
CTCs from before to after treatment
in patients given cisplatin-paclitaxel
plus bevacizumab, the lower the risk of
death (HR, 0.87), he said.
Dr. Tewari disclosed that he is a consultant to Genentech/Roche, Advaxis,
and Caris Life Sciences; receives honoraria/reimbursement or grants from
Genentech/Roche; and performs research for Caris Life Sciences.
[email protected]
The views you value.
Visit oncologypractice.com
Volume 12 • Number 1 • January 2014
ORIGINAL REPORTS
Understanding the experience of living with non–small-cell lung cancer: a qualitative study
Joanne Buzaglo et al, p. 6
Vitamin D deficiency in the oncology setting
Debra M. DeMille et al, p. 13
REVIEWS
Current options and future directions in the systemic treatment of metastatic melanoma
Katja Schindler & Michael A Postow, p. 20
Biomarker testing for treatment of metastatic colorectal cancer: role of the pathologist in
community practice
Rafael Rodriguez, p. 27
COMMUNITY TRANSLATIONS
Afatinib in metastatic NSCLC with mutations
Edited by Jame Abraham, p. 4; with Commentary by James M Stevenson, p. 2
CASE REPORTS
A ‘double-hit’ bone marrow rare co-occurrence of 2 different pathologies
Adham Jurdi et al, p. 33
Including features on synthetic lethality (p. 35) and practical biostatistics (p. 40)
www.jcso-online.com
Complete table of contents, page A11
GYNECOLOGIC MALIGNANCIES
The news you need.
The research that matters.
DR. KRISHNANSU S. TEWARI
18
May 2015 • The Oncology Report
Sentinel node mapping detects nodal
spread of endometrial cancer
VITALS
GYNECOLOGIC MALIGNANCIES
Key clinical point: SLN mapping performs similarly to LND
for detecting stage IIIC disease
in women with endometrial
cancer.
Major finding: SLN mapping
had a higher detection rate
of stage IIIC1 disease in lowrisk disease (4.8% vs. 1.8%)
and a similar detection rate
of stage IIIC disease overall
in intermediate- and high-risk
disease.
Data source: Two retrospective
cohort studies of 1,135 women with low-risk endometrial
cancer and 412 women with
intermediate- or high-risk endometrial cancer.
Disclosures: Dr. Eriksson
disclosed that she had no
relevant conflicts of interest.
Dr. Ducie disclosed that she
had no relevant conflicts of
interest.
DR. ANE GERDA ZAHL ERIKSSON
BY SUSAN LONDON
AT THE A N N U A L ME E TI N G O N WO ME N ’ S C A N C E R
CHICAGO – Sentinel lymph node mapping is a safe, less extensive alternative
to lymph node dissection in women
with endometrial cancer regardless of
the clinically suspected risk of metastases, suggest a pair of retrospective
cohort studies reported at the annual
meeting of the Society of Gynecologic
Oncology.
“The role and extent of surgical staging in endometrial carcinoma is controversial. The various strategies range
from no lymphadenectomy to a full
lymphadenectomy dissection up to the
renal vessels,” said Dr. Ane Gerda Zahl
Eriksson, a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, New York.
“The use of SLN [sentinel lymph
node] mapping is emerging as an acceptable approach for nodal assessment
in endometrial carcinoma. However, as
always when introducing a novel management strategy, we must be mindful
not to compromise oncologic outcome
or otherwise inflict harm on our patients by our approach,” she added.
Dr. Eriksson and colleagues assessed
clinicopathologic outcomes according
to nodal assessment approach among
women with low-risk endometrial cancer, defined as that with endometrioid
histology of any grade with myometrial
invasion of less than 50%.
They compared 493 women who had
selective lymph node dissection (LND)
at the Mayo Clinic between 2004 and
2008 according to an institutional algorithm (complete pelvic and para-aortic
lymphadenectomy to the renal veins
in cases deemed at risk for nodal metastasis) with 642 women who had
SLN mapping at the Memorial Sloan
Kettering Cancer Center between 2006
and 2013 according to an institutional
algorithm. The SLNs were evaluated
by pathologic ultrastaging and were
considered positive whether they had
macrometastases, micrometastases, or
isolated tumor cells.
Results showed that patients in the
SLN cohort were more likely to have
pelvic nodes excised (93% vs. 58%) and
less likely to have para-aortic nodes
excised (14% vs. 50%), Dr. Eriksson reported.
Markedly fewer lymph nodes were
removed per patient with the SLN algorithm, yet it yielded a higher detection
rate of stage IIIC1 disease (4.8% vs.
1.8%) and similar detection rates of
stage IIIA/B and stage IIIC2 disease.
Patients in the SLN cohort were more
than twice as likely to receive adjuvant
therapy (27% vs. 12%). (Dr. Eriksson
noted that patients in the SLN cohort
who had positive nodes were offered the
same adjuvant therapy options regardless of the amount of metastases found
in the nodes.)
With a median follow-up of 2.1 years
in the SLN cohort and 3.5 years in the
LND cohort, the cohorts had statistically indistinguishable 3-year rates of
freedom from isolated nodal recurrence
(99.6% in each) and disease-free survival
(94.9% and 96.8%).
“The application of the SLN algorithm does not appear to compromise
oncologic outcome in this short follow-up. The value of SLN dissection or
selective lymphadenectomy in patients
with tumors equal to or less than 2 cm
remains controversial,” Dr. Eriksson
commented. “The clinical significance
of disease detected on ultrastaging and
the role of adjuvant therapy in these patients remains to be determined.”
“Prospective assessment of the SLN
algorithm is needed and underway,” she
concluded. “Our findings support the
use of either strategy for endometrial
cancer staging with no apparent detriment to the SLN algorithm.”
In the second study, investigators led
by Dr. Jennifer A. Ducie, also a surgical
fellow in gynecologic oncology at the
Memorial Sloan Kettering Cancer Center, performed a similar analysis among
oncologyreport.com19
women with intermediate-risk endometrial cancer, defined as that having endometrioid histology with any grade and
at least 50% myometrial invasion, and
high-risk endometrial cancer, defined as
serous or clear cell carcinoma.
In the intermediate-risk group, there
were 82 patients in the SLN cohort and
107 patients in the LND cohort. The
groups had a similar detection rate
of stage IIIC disease overall (35% and
28%), but the SLN cohort had a higher
rate of detection of stage IIIC1 disease
(32% vs. 11%) and the LND cohort had
a higher rate of detection of stage IIIC2
disease (17% vs. 4%), Dr. Ducie reported.
In the high-risk group, there were 120
patients in the SLN cohort and 103 patients in the LND cohort. Patients in the
SLN cohort were more likely to have
pelvic nodes removed (98% vs. 85%) but
had fewer nodes removed (11 vs. 30).
Among patients who had para-aortic
nodes removed, the SLN cohort was
similarly as likely as the LND cohort to
have positive nodes, but had a smaller
median number positive (two vs. five).
The rate of detection of stage IIIC disease overall (23% vs. 19%) and of the
substages was statistically indistinguishable.
“Though both strategies yield similar
detection rates of stage IIIC disease, it
remains to be determined if removal of
more normal-appearing lymph nodes
will improve survival,” Dr. Ducie concluded. “A limitation of this portion of
our collaborative study is that we don’t
address adjuvant therapy or outcomes,
but these will be addressed in future
analyses.”
DR. JENNIFER A. DUCIE
[email protected]
SCORPION: Interval debulking is safer in
advanced ovarian cancer
BY SUSAN LONDON
AT THE ANNUAL MEETING ON WOMEN’S CANCER
VITALS
Key clinical point: Complications were much less common
with interval debulking than
with primary debulking.
Major finding: The odds of
major perioperative morbidity
were 19.3 times higher with
primary debulking than with
neoadjuvant chemotherapy followed by interval debulking.
Data source: Interim results of
a randomized phase III trial
among 110 patients with ovarian cancer and a high tumor
load.
Disclosures: Dr. Fagotti disclosed that she had no relevant conflicts of interest.
GYNECOLOGIC MALIGNANCIES
CHICAGO – Delaying debulking until
patients have had some chemotherapy is a safer strategy for women with
advanced ovarian cancer, according to
interim results of the randomized phase
III SCORPION trial (Surgical Complications Related to Primary or Interval
Debulking in Ovarian Neoplasm).
The odds of complications such as
sepsis, organ failure, and death in the
perioperative period were 19.3 times
higher among women who underwent
primary debulking than among counterparts who underwent neoadjuvant
chemotherapy followed by interval
debulking, Dr. Anna Fagotti reported
at the annual meeting of the Society of
Gynecologic Oncology.
“Primary debulking surgery is associated with a statistically significantly
higher risk of major perioperative morbidity with respect to interval debulking
surgery in high–tumor load advanced
epithelial ovarian cancer patients,” she
said.
“Most of these complications, however, are grade 3, with a higher incidence
than reported from retrospective analyses in the literature. The reported mortality rate [with primary debulking] …
is in line with the literature data,” added
Dr. Fagotti of the University of Perugia, Terni, Italy. “Our survival data will
definitely clarify whether such a severe
complication rate is acceptable in terms
of cost-effectiveness.”
The trial also offers a cautionary note
about study methodology in this setting, she said. Specifically, “any neoadjuvant chemotherapy clinical study that
is based on instrumental or clinical evaluation only, excluding staging laparoscopy, might include very heterogeneous
populations, thus leading to substantial
biases.”
Giving some background to the research, Dr. Fagotti noted that case series
20
May 2015 • The Oncology Report
GYNECOLOGIC MALIGNANCIES
DR. ANNA FAGOTTI
have shown a survival advantage for
women with advanced ovarian cancer
who undergo primary debulking with
optimal or no residual tumor, albeit at
the cost of more extensive surgery. But
randomized trials have shown similar
survival and fewer complications with
the interval debulking approach.
“We know also that many limits can
be ascribed to these studies, so, as a consequence, there are gray-zone patients
in whom the best primary treatment option is not clear yet,” she commented.
The 110 patients studied in SCORPION had suspected advanced ovarian
cancer with a FIGO (International Federation of Gynecology and Obstetrics)
stage of IIIc or IV, and had an intraoperative staging laparoscopy score of
8-12. They were randomized evenly to
primary debulking followed by adjuvant
chemotherapy or to neoadjuvant chemotherapy followed by interval debulking.
Three patients in the latter arm had
progression during their chemotherapy
and were therefore unable to proceed
to their planned surgery, Dr. Fagotti reported.
On average, women in the interval
debulking group had less extensive surgery than peers in the primary debulking group. In particular, they were
significantly less likely to undergo pelvic
and/or abdominal peritonectomy (58%
vs. 100%), bowel resection (19% vs.
100%), diaphragmatic peritonectomy or
resection (38% vs. 100%), partial hepatectomy (0% vs. 18%), and splenectomy
(4% vs. 53%). Overall, they were nearly
half as likely to have any upper abdominal procedure (58% vs. 100%).
Ninety percent of all patients had
optimal cytoreduction to residual disease of 1 cm or less, with no significant
difference between groups, Dr. Fagotti
said.
In terms of surgical measures, the
interval debulking group had a median
operative time that was about a third
shorter and median blood loss and hospital stays about half those with primary debulking.
The interval debulking group was
significantly less likely to experience any
major postoperative complication (6%
vs. 53%, P = .001). Notably, they had
lower rates of pleural effusion (2% vs.
31%), sepsis (0% vs. 7%), pulmonary
thromboembolism (0% vs. 6%), reoperation with organ resection (0% vs. 4%),
multiorgan failure (0% vs. 2%), and surgery-related death (0% vs. 4%).
[email protected]
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oncologyreport.com21
HPV-targeted TILs trigger CR in some
advanced cervical cancer patients
BY MITCHEL L. ZOLER
FROM JOURNAL OF CLINICAL ONCOLOGY
T
VITALS
Key clinical point: In a pilot
study of nine patients with
metastatic cervical cancer, a
single infusion of tumor-infiltrating lymphocytes selected
for reactivity against human
papillomavirus oncoproteins
produced two complete responses.
Major finding: Objective tumor
responses occurred in three of
nine treated patients, with two
complete responders and one
partial responder.
Data source: Case series of
nine patients treated at a single U.S. center.
Disclosures: Dr. Hinrichs has
patents pending for methods
of lymphocyte preparation
and has an immediate family member who is employed
by MedImmune.
GYNECOLOGIC MALIGNANCIES
reatment of nine women with
metastatic cervical cancer with
single infusions of tumor-infiltrating lymphocytes grown out from
tumor specimens collected from each
patient resulted in two complete responses and one partial response, suggesting that this form of adoptive T-cell
therapy could potentially help woman
with this type of advanced, solid tumor.
“These results may have important
implications for immunotherapy of
cervical cancer and for the expanded
application of cellular therapy,” wrote
Sanja Stevanovic, Ph.D., and her associates in an article published online
( J. Clin. Oncol. 2015 [doi:10.1200/
JCO.2014.58.9093]).
The findings “advance the field by
demonstrating that the durable, complete tumor regression observed with
cellular therapy for melanoma and B-cell
malignancies is also possible for an epithelial cancer,” said coauthor Dr. Christian S. Hinrichs in an interview. “It is a
scientific proof-of-principle. To build on
these findings, we are studying the same
approach in other HPV- [human papillomavirus] positive cancers including
throat and anal cancer. In addition, we
are developing T-cell-receptor gene therapies that target the HPV oncoproteins
for patients with HPV-positive cancers.
A clinical trial using this strategy is now
open,” said Dr. Hinrichs, an oncologist in
the surgery branch of the U.S. National
Cancer Institute in Bethesda, Md.
The role HPV plays in the pathogenesis of cervical cancer gave Dr. Hinrichs
and his associates a unique target to
exploit for developing adoptive cell
therapy (ACT) with tumor-infiltrating
lymphocytes (TILs) for women with
metastatic cervical cancer.
Immunotherapy “is an attractive strategy for cervical cancers because these
tumors nearly universally harbor the
HPV E6 and E7 antigens,” they wrote in
their report. “The patients in this study
had cancers that constitutively expressed
the HPV oncoproteins and the administered T cells were selected to target
these antigens.”
In fact, they determined that the
HPV-reactivity of the TILs that the
patients received and the frequency of
HPV-reactive T cells in patients’ peripheral blood after treatment correlated
with the tumor responses of each patient.
“The main difference between this
and other protocols for generating TILs
is that we generated multiple, individual
TIL cultures from tumor fragments,
and tested the T cells in each culture for
their reactivity against HPV oncoproteins,” explained Dr. Hinrichs. “The vast
majority of other cancer types do not
permit this approach because they do
not have antigens like the HPV oncoproteins that are almost always expressed
by the tumors but absent from healthy
tissues.”
The researchers enrolled patients
during April 2012-May 2014. Patients
averaged 37 years old, and included
women with squamous-cell carcinomas,
adenocarcinomas, or adenosquamous
carcinomas. Seven women had tumors
associated with HPV-18, and two had
HPV-16 involvement. All patients had
multiple sites of distant metastases and
had previously received platinum chemotherapy; six had received combination chemotherapy. Patients received a
median of 80 x 109 TILs.
The two women with a complete
response to their ACT had an ongoing response after 15 and 22 months,
respectively. One of these patients had
a squamous-cell carcinoma, the other
an adenocarcinoma. None of the nine
patients showed any acute toxicity
related to ACT, nor did they have any
autoimmune adverse events. The most
common severe toxicities were hematologic and were the expected result of
the lymphocyte-depleting conditioning
regimen used.
22
May 2015 • The Oncology Report
“
It is a scientific
proof-ofprinciple.
As of April 2015, no ACT has received U.S. Food and Drug Administration approval for routine use. Although
many types of ACT for various cancers are under study they all remain
investigational, Dr. Hinrichs said. A
recent review of ACT by two National
Cancer Institute researchers who collaborated on the cervical cancer study
highlighted some of the logistical
challenges that ACT presents (Science
2015;348:62-8).
ACT “is a more complex approach to
the delivery of cancer treatment than
many other types of immunotherapy
and has often been criticized as impractical and too costly for widespread application,” the review noted. The “highly
personalized” treatments involved
do not fit the traditional paradigm of
off-the-shelf reagents. The authors of
the review proposed that one possible
solution is to have centralized facilities
for producing TILs or other genetically
modified lymphocytes that can then
provide these personalized cells for ACT
performed at local centers.
[email protected]
On Twitter @mitchelzoler
VIEW ON THE NEWS
Promising therapy faces logistical hurdles
GYNECOLOGIC MALIGNANCIES
T
he new report on treating nine women with
metastatic cervical cancer with adoptive T-cell
therapy and seeing complete responses in two patients is an important proof-of-concept in a small
group of patients. This represents a significant advance for this approach to treatment because until
now, most adoptive T-cell therapy studies involved
hematologic malignancies or melanoma. Metastatic cervical cancer is a bad and hard-to-treat disease,
and finding a treatment that can halt its progression is very promising news for patients with any
type of progressive, advanced solid tumor.
But treating patients with tumor infiltrating lymphocytes and adoptive T-cell therapy (ACT) is not
for the faint hearted. Isolating and expanding a line
of T cells that are specific for a particular tumor
antigen requires a very high degree of technical expertise that is not widely available. It requires hospitals performing this work to have facilities that
mimic those found at pharmaceutical companies.
The high level of resources required to safely and
successfully offer this treatment cannot be available
everywhere.
These technical limitations have led to development of two related strategies: T-cell recep-
tor–engineered T cells, and chimeric-antigen
receptor–modified T cells. Perhaps the most advanced example today of these approaches is the
chimeric antigen receptor–modified T cells that
target the CD19 antigen, which have been highly
active for treating acute myelogenous leukemia
and acute lymphoblastic leukemia, with response
rates approaching 90%. My group has been actively
working on developing treatment based on T-cell
receptor–engineered T cells.
The ACT approach used in the new study with
cervical cancer patients suggests that targeting the
human papillomavirus oncoproteins E6 and E7
may also have relevance for treating other types of
human cancers related to human papillomavirus,
such as cancers of the anus, oropharynx, penis, vagina, and vulva.
Dr. Kunle Odunsi is deputy director and chair of the
department of gynecologic oncology at Roswell Park
Cancer Institute in Buffalo, and professor of gynecology
and obstetrics at the State University of New York at
Buffalo. He had no relevant disclosures. He made these
comments in an interview, and in an editorial accompanying the report by Dr. Stevanovic et al (J. Clin. Oncol.
2015 [doi:10.1200/JCO.2014.60.6566]).
Listen to Dr Henry's monthly podcast
to stay up to date on the latest research and reviews from
The Journal of Community and Supportive Oncology.
24
May 2015 • The Oncology Report
AACR: Metformin survival benefit shaky in
pancreatic cancer
VITALS
GASTROINTESTINAL MALIGNANCIES
Key clinical point: Metformin
use may not improve pancreatic cancer survival.
Major finding: Median survival was 8.1 months without
metformin vs. 11.4 months if
metformin started less than
30 days after cancer diagnosis
and 13.7 months if started
more than 30 days after diagnosis.
Data source: Retrospective
cohort of 1,360 patients with
pancreatic cancer and diabetes.
Disclosures: The study was
funded by grants from the
Mayo Clinic. Dr. Chaiteerakij
reported having nothing to
disclose.
DR. ROONGRUEDEE CHAITEERAKIJ
BY PATRICE WENDLING
FR O M TH E A A C R A N N U A L M E E TI N G
A
detailed survival analysis questions the rationale behind use of
the diabetes drug metformin to
improve pancreatic cancer survival.
Several epidemiologic studies have
shown that metformin use reduces cancer mortality, leading the diabetes drug
to be included in the treatment arm
of 20 open clinical trials in recalcitrant
cancers, Dr. Roongruedee Chaiteerakij
reported at the annual meeting of the
American Association for Cancer Research.
The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,”
which may have introduced unintended
biases.
To address these potential biases, Dr.
Chaiteerakij and her colleagues at the
Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC)
and diabetes between 2000 and 2011 in
the database of the Mayo Clinic Specialized Programs of Research Excellence
(SPORE) in Pancreatic Cancer. More
than half (59%) were male; the average
age was 67 years.
A total of 380 patients were excluded
for surgically induced diabetes, unknown diabetes duration, and PDAC
diagnosis more than 90 days prior to the
first Mayo visit. This left 980 patients in
the final cohort.
An initial analysis using the ever vs.
never classification suggested that metformin use was associated with marginally improved survival in patients with
PDAC (median 9.9 months ever use vs.
8.9 months never use; unadjusted hazard
ratio, 0.9; P = .08), Dr. Chaiteerakij said.
The association was most significant
in locally advanced PDAC patients (10.2
months ever use vs. 8.1 months never
use; unadjusted HR 0.7; P = .006).
The investigators then performed a
subanalysis of locally advanced PDAC
patients, this time stratified by timing of
metformin initiation: never used (reference group), started more than 1 year
before PDAC diagnosis, started within 1
year before PDAC diagnosis, started less
than 30 days post PDAC diagnosis, and
started more than 30 days post PDAC
diagnosis.
Median survival was 8.1, 10.1, and
9.9 months in the first three groups,
increasing to 11.4 months and 13.7
months in the two groups that started
metformin after PDAC diagnosis, Dr.
Chaiteerakij reported.
Hazard ratios for the four metformin
groups were 0.7, 0.6, 0.9, and 0.5, after
adjustment for age, sex, disease stage,
body mass index, and diagnosis year.
The increased survival in patients who
started metformin after PDAC diagnosis demonstrates the inherent survival
bias in ever/never classification because
these patients had lived long enough to
receive the drug, she said.
The ever/never classification is commonly used because it can be difficult
to extract detailed information on drug
use, dose, or timing from retrospective
medical records, she noted in a press
briefing.
“Epidemiologic studies of medication
exposure and cancer survival warrant
very careful and detailed data collection
and analysis to minimize biases,” Dr.
Chaiteerakij concluded. “Researchers
should exercise caution when initiating
clinical trials based on retrospective epidemiologic studies.”
That said, 11 pancreatic cancer trials
are currently listed on www.clinicaltrials.gov, she told reporters.
A simple search of the site for “cancer
and metformin” yields no fewer than
230 trials.
It isn’t possible to say at this time
whether the Mayo results are applicable
to other nonrecalcitrant cancers, Dr.
Chaiteerakij said.
[email protected]
On Twitter @pwendl
oncologyreport.com25
Biomarker correlates with pancreatic
cancer severity
BY NEIL OSTERWEIL
AT SSO 2015
Markers lacking
PDAC is a highly aggressive cancer with
a propensity for early invasion and metastasis. More than half of all patients
(53%) have metastatic disease at the
time of diagnosis, and 5-year survival
for these patients is only 2.3%, according to the Surveillance, Epidemiology,
and End Results (SEER) cancer statistics
review for 2014, she noted.
The only currently available clinical
biomarker for PDAC, carbohydrate antigen 19-9 (CA 19-9), generally correlates
with treatment response and disease
recurrence but has low sensitivity and
specificity, Dr. Marayati said.
Circulating tumor cells (CTCs) – cells
shed from the primary tumor into circulation – hold promise for better detection of cancer, but CTCs from pancreat-
[email protected]
VITALS
Key clinical point: GJB3 may
be a serum marker for metastatic pancreatic ductal adenocarcinoma.
Major finding: GJB3 was expressed at significantly higher
levels in patients with metastatic vs. localized PDAC.
Data source: Gene expression
analyses involving patient tumor samples and 11 pancreatic cancer cell lines.
Disclosures: The study funding
source was not disclosed. Dr.
Marayati reported having no
disclosures.
DR. RAOUD MARAYATI
GASTROINTESTINAL MALIGNANCIES
HOUSTON – A circulating biomarker
has the potential to identify metastatic
pancreatic cancer and may be able to
predict prognosis, investigators said.
Levels of a gene encoding for the
gap-junction beta 3 (GJB3) protein were
highly elevated in both pancreatic cancer cell lines and in blood samples from
patients with pancreatic ductal adenocarcinoma (PDAC), but the gene was undetectable in blood samples from patients
without cancer, reported Dr. Raoud
Marayati from the Lineberger Comprehensive Cancer Center at the University
of North Carolina, Chapel Hill.
An analysis of gene expression in
tumors from patients with PDAC also
showed that patients with tumors expressing higher levels of GJB3 had significantly worse overall survival rates.
“GJB3 is highly expressed in blood
samples from patients with metastatic
versus local pancreatic cancer. GJB3 is a
potential circulating biomarker for metastatic pancreatic cancer,” Dr. Marayati
said at the annual Society of Surgical
Oncology Cancer Symposium.
ic tumors have proven to be extremely
difficult to isolate and count, she added.
To see whether they could identify
circulating biomarkers of metastatic
PDAC, Dr. Marayati and colleagues
working in the laboratory of Dr. Jen
Jen Yeh at the university first identified
76 genes that are differentially overexpressed in metastatic PDAC tumors,
compared with localized primary tumors and with normal tissues.
The investigators looked for expression of the genes in 11 pancreatic cancer
cell lines and in blood samples from 20
patients with pancreatic cancer and four
without cancer. As noted, one gene,
GJB3, was highly expressed in all of the
cell-line samples but could not be detected in white blood cells from patients
without PDAC.
To validate GJB3 as a potential cancer
marker, the authors looked at expression levels in circulating tumor cells and
found that, among the patients with
cancer, expression levels of GBJ3 were
significantly higher in those with metastatic disease, compared with localized
disease (P = .016).
“That would suggest that GJB3 is a
potential circulating biomarker specifically for metastatic pancreatic cancer
patients,” Dr. Marayati said.
The investigators hypothesized that
GJB3 may play a role in the biology of
pancreatic cancer metastasis. To test this
idea, they looked at resected tumors
from 131 patients with primary pancreatic cancer and found that high tumor
expression of GJB3 was associated with
worse survival. Median overall survival
among 32 patients with low levels of
gene expression in their tumors was 24
months, compared with 15 months for
99 patients with high levels of GJB3 expression (P = .031).
The investigators plan to further validate the marker by testing it with larger
samples from both patients with pancreatic cancer and controls.
26
May 2015 • The Oncology Report
Ramucirumab approval expanded to include
metastatic colorectal cancer indication
BY ELIZABETH MECHCATIE
T
13.3
GASTROINTESTINAL MALIGNANCIES
months median
overall survival
(OS) among
those on
ramucirumab.
he Food and Drug Administration has expanded approval of
the antiangiogenic agent ramucirumab for use in combination with
FOLFIRI for “the treatment of metastatic colorectal cancer (mCRC) with
disease progression on or after prior
therapy with bevacizumab, oxaliplatin,
and a fluoropyrimidine,” according to
the updated prescribing information.
The FDA announced the expanded
approval on April 24 in a statement,
which said that it was based on the results of an international study of 1,072
patients with mCRC that progressed
during or within 6 months of discontinuing bevacizumab-, oxaliplatin- and
fluoropyrimidine-based combination
chemotherapy, randomized to treatment with FOLFIRI alone, or to FOLFIRI plus ramucirumab. Their median age
was 62 years, almost 60% were men,
and 99% had an ECOG performance
status of 0 or 1. In both arms, treatment
was administered every 2 weeks; the
dose of ramucirumab was 8mg/kg, administered by an intravenous infusion
every 2 weeks, and was continued until
disease progressed or toxicity became
unacceptable.
Median overall survival (OS), the
primary endpoint, was 13.3 months
among those on ramucirumab, vs. 11.7
months among those on placebo. The
improvement in OS was statistically
significant (P = .023), with a reduced
risk of 15%. Compared with those on
FOLFIRI alone, there was also a significant improvement in progression-free
survival (PFS) among those treated
with the combination, a median of 5.7
months vs. 4.5 months (P < 0.001) and a
reduced risk of 21%.
“In general, the safety data was consistent with the known safety profile
established in previously approved indications,” although thyroid monitoring
identified hypothyroidism in 2.6% of patients, according to the statement. The
label includes a boxed warning about
the risks of hemorrhage, gastrointestinal perforation, and impaired wound
healing associated with treatment.
Ramucirumab is a human vascular
endothelial growth factor receptor 2
(VEGFR2) antagonist, marketed as
Cyramza by Eli Lilly. It was initially approved for advanced gastric cancer and
gastroesophageal junction adenocarcinoma, and metastatic non–small cell
lung cancer indications in late 2014.
Serious adverse events associated with
treatment should be reported to the
FDA’s MedWatch program at 800-3321088 or online https://www.accessdata.
fda.gov/scripts/medwatch/.
[email protected]
oncologyreport.com27
Laparoscopic resection ‘noninferior’ to
open approach for rectal cancer
BY MARY ANN MOON
L
FROM TH E NEW ENGLAND
JOURNAL OF MEDICINE
[email protected]
VITALS
Key clinical point: Laparoscopic resection is noninferior to
open surgery in preventing locoregional recurrence of rectal
cancer and improving survival.
Major finding: At 3-year follow-up, the rate of locoregional
recurrence was identical between the laparoscopic- and
the open-surgery groups, at
5% each.
Data source: An industry-sponsored multicenter open-label
noninferiority trial comparing
laparoscopic to open resection
of rectal cancer in 1,044 patients followed for 3 years.
Disclosures: The trial was
funded by Ethicon Endo-Surgery Europe, a subsidiary
of Johnson & Johnson; the
Swedish Cancer Society; the
Health and Medical Care Committee of Region Vastra Gotaland; Sahlgrenska University
Hospital; Erasmus University
Medical Center; Dahousie
University; and VU University
Medical Center. Dr. Bonjer
reported having no disclosures;
two of his associates reported
ties to AbbVie, Merck Sharp
& Dohme, Takeda,Johnson &
Johnson, Covidien, Olympus
Medical, and Applied Medical.
GASTROINTESTINAL MALIGNANCIES
aparoscopic resection of rectal
cancer is noninferior to open surgery in preventing locoregional
recurrence and in improving overall
and disease-free survival, according to
a report published online April 1 in the
New England Journal of Medicine.
The laparoscopic approach has increasingly replaced open surgery in
recent years, primarily because it offers
short-term advantages such as less pain,
reduced blood loss, and a shorter recovery time. But no large randomized
trials have established that long-term
outcomes with laparoscopic resection,
including survival, are at least noninferior to those with open surgery, said Dr.
Hendrik Jaap Bonjer of VU University
Medical Center, Amsterdam, and his
associates.
They now report the 3-year outcomes
of the Colorectal Cancer Laparoscopic
or Open Resection (COLOR) II trial, an
industry-sponsored noninferiority study
performed at 30 medical centers in
eight countries in Europe, North America, and Asia. The trial involved 1,044
patients who had solitary, noninvasive
adenocarcinomas of the rectum within
15 cm of the anal verge. A total of 699
of the study participants were randomly assigned to laparoscopic and 345 to
open surgery.
At 3-year follow-up, the rate of locoregional recurrence was identical
between the two study groups, at 5%
each. In addition, rates of disease-free
survival slightly favored the laparoscopic approach (74.8%) over the open
approach (70.8%), as did rates of overall
survival (86.7% and 83.6%, respectively)
and rates of distant metastases (19.1%
and 22.1%, respectively). Patients with
stage III disease appeared to benefit
the most from laparoscopic surgery,
with disease-free survival of 64.9% vs.
52.0%, the investigators said (N. Engl.
J. Med. 2015 April 1 [doi:10.1056/NEJMoa1414882]).
These findings support the idea that
the reduced surgical trauma associated with laparoscopic techniques may
decrease tumor recurrence, perhaps
by attenuating stress responses and preserving immune function, they noted.
“In our study, laparoscopic surgery in
patients with cancer in the lower third
of the rectum was associated with a
lower rate of involved circumferential
resection margin and a lower locoregional recurrence rate than was open
surgery. During laparoscopic surgery,
narrow spaces such as the lower pelvis are better visualized than in open
surgery, owing to the use of a laparoscope, which projects a magnified and
well-illuminated image of the operative
field on the monitors. A clear view is of
paramount importance to accomplish
a resection of the cancer with sufficient
margins,” Dr. Bonjer and his associates
added.
The trial was funded by Ethicon
Endo-Surgery Europe, a subsidiary of
Johnson & Johnson; the Swedish Cancer
Society; the Health and Medical Care
Committee of Region Vastra Gotaland; Sahlgrenska University Hospital;
Erasmus University Medical Center;
Dahousie University; and VU University
Medical Center. Dr. Bonjer reported
having no disclosures; two of his associates reported ties to AbbVie, Merck
Sharp & Dohme, Takeda, Johnson &
Johnson, Covidien, Olympus Medical,
and Applied Medical.
28
May 2015 • The Oncology Report
AACR: Targeted combo active in triplenegative breast cancer, ovarian cancer
VITALS
BREAST CANCER
Key clinical point: Combining
the PARP inhibitor olaparib
and the investigational P13K
inhibitor BKM 120 is safe and
active in triple-negative breast
cancer and ovarian cancer in
early studies.
Major finding: Partial responses
occurred in 26% of patients
with ovarian cancer and 21%
with breast cancer.
Data source: Phase I study in
70 women with ovarian cancer
or breast cancer.
Disclosures: The study was
funded by Stand Up to Cancer, the Kathryn Fox Samway
Foundation, and participating
centers. Olaparib was provided
by AstraZeneca and BKM120
by Novartis. Dr. Matulonis
reported research funding
from AstraZeneca, as well as
renumeration for attending a
speaker’s bureau.
BY PATRICE WENDLING
FR O M TH E A A C R A N N U A L M E E TI N G
C
ombining the poly(ADP-ribose)
polymerase inhibitor olaparib
and the investigational P13K inhibitor BKM 120 was safe and active in
triple-negative breast cancer and ovarian
cancer in a phase I trial.
Patients with both BRCA-mutant and
BRCA-wildtype breast cancer responded
to the combination. One patient with
germline BRCA-wildtype triple-negative
breast cancer (TNBC) and lung metastases had a partial response and remained
on treatment for 20 cycles, or nearly 2
years, study author Dr. Ursula Matulonis reported at the annual meeting of
the American Association for Cancer
Research.
Rationale for the study lay in data
from mouse models showing that combination olaparib and BKM120 was
more effective than either drug alone
in BRCA-mutant breast cancer and
BRCA-wildtype TNBC. Similarities also
exist between high-grade serous ovarian
cancer and TNBC, including an association with germline BRCA mutations,
sensitivity to platinum agents, and high
copy number alteration rates, she said
in a press briefing at the meeting.
Olaparib (Lynparza), a PARP (poly
[ADP-ribose] polymerase) inhibitor, was
approved in the United States in December 2014 for treating BRCA-positive
advanced ovarian cancer.
The phase I, dose-escalation study
enrolled 70 patients with a diagnosis
of recurrent high-grade serous ovarian
cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.
The histology was high-grade serous
in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma,
and 4% poorly differentiated carcinoma.
Most of the 24 breast cancer patients
(63%) had TNBC, while 29% had estrogen receptor–positive/progesterone
receptor–positive disease and 8% had
ER+/PR– breast cancer.
Germline BRCA mutations were
present in 77% of ovarian and 58% of
breast cancer patients. The median age
in the two groups was 60 years and
47.5 years, respectively. Prior PARP or
P13kinase pathway inhibitors were allowed during dose escalation. Among
ovarian cancer patients, 12 (26%) had a
partial response and 22 (48%) had stable disease. Responses were similar in
the breast cancer group, with 5 (21%)
partial responses and 12 (50%) patients
with stable disease, said Dr. Matulonis
of the Dana-Farber Cancer Center
and Harvard Medical School, both in
Boston.
Ten dosing regimens were evaluated
in the study, beginning with an initial
dose of BKM120 60 mg once daily and
olaparib 100 mg twice daily, both given
orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs)
– grade 3 hyperglycemia and grade 3
transaminitis – and prompted the investigators to back down to dose levels of
40 mg and 50 mg, respectively.
No DLTs occurred until dosing
reached BKM120 60 mg and olaparib
300 mg, at which point one grade-4
transaminitis and one grade-3 depression were reported in cycle 2, she said.
Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.
As for why the two DLTs occurred at
the initial dose but the same doses were
later used without incident, Dr. Matulonis said that one of the patients with a
DLT fell out of well-controlled diabetes
and the other had liver metastases that
accelerated during treatment.
Overall, the most common nonhematologic toxicities of any grade were
nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic
toxicities of any grade were anemia in
23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in
10% of patients.
oncologyreport.com29
“Combinations of biologic agents will
require establishment of target patient
populations using biomarkers in order
to predict sensitivity as well as determine mechanisms of resistance,” Dr.
Matulonis concluded.
Next-generation sequencing is ongoing for BKM120/olaparib patients and
mechanisms of response and resistance
are being studied in human ovarian
mouse models, she added.
26%
The study was funded by Stand Up
to Cancer, the Kathryn Fox Samway
Foundation, and participating centers.
Olaparib was provided by AstraZeneca
and BKM120 by Novartis. Dr. Matulonis
reported research funding from AstraZeneca, as well as renumeration for
attending a speaker’s bureau.
had a partial
response in the
ovarian cancer
patients.
[email protected]
On Twitter @pwendl
Exercise pumps up chemotherapy
completion rates for breast cancer patients
FROM JOURNAL OF CLINICAL ONCOLOGY
C
ompared with usual care, a
moderate- to high-intensity exercise intervention had beneficial
effects on chemotherapy completion
rates, symptom burden, and return-towork rates among women with breast
cancer who were undergoing adjuvant
chemotherapy, according to a study
published online April 27 in the Journal
of Clinical Oncology.
For the multicenter Physical Exercise
During Adjuvant Chemotherapy Effectiveness Study (PACES), 230 women
(mean age 51 years) with breast cancer
who were undergoing adjuvant chemotherapy were randomized to participate
in a high- to moderate-intensity exercise
program supervised by physical therapists (n = 76), a low-intensity homebased program (n = 77), or the usual
care group (n = 77).
VITALS
Dose adjustments in the chemotherapy regimen were less frequent in the
moderate- to high-intensity exercise
group (12%) than in the usual care or
low-intensity groups (both 34%, P =
.002). Patients in the exercise interventions were more likely to return to work
by the 6-month follow up than those
with usual care, wrote Ms. Hanna van
Waart, a doctoral candidate at the Netherlands Cancer Institute, Amsterdam,
and colleagues ( J. Clin. Oncol. 2015 Apr.
27 [doi:10.1200/JCO.2014.59.1081]).
“This not only has financial implications, but also carries meaning in terms
of quality of life and a sense of return
to normalcy,” they wrote.
At completion of chemotherapy, patients from both activity groups reported
significantly better physical functioning,
less nausea and vomiting, and less pain
than did those in the usual care group.
[email protected]
BREAST CANCER
Key clinical point: Moderateto high-intensity exercise
during adjuvant chemotherapy
improves completion rates.
Low-intensity physical activity
resulted in less pronounced
benefits.
Major finding: Dose adjustments in the chemotherapy
regimen were less frequent in
the moderate- to high-intensity
exercise group (12%) than in
the usual care or low-intensity
groups (both 34%, P = .002).
Data source: PACES, a controlled multicenter study that
randomized 230 patients with
breast cancer to participate
in high- to moderate-intensity
(n = 76) or low intensity (n =
77) exercise or usual care (n =
77) while undergoing adjuvant
chemotherapy.
Disclosures: Dr. van Waart reported having no disclosures.
Two of her coauthors reported
ties to several industry sources.
©Luka8au /thinkstockphotos.com
BY JENNIFER KELLY SHEPPHIRD
30
May 2015 • The Oncology Report
Oophorectomy improves survival after
breast cancer in BRCA1 carriers
VITALS
BREAST CANCER
Key clinical point: Oophorectomy significantly improved
the prognosis of women with
breast cancer and a BRCA1
mutation.
Major finding: The adjusted
hazard ratio for breast cancer mortality in women with
a BRCA1 mutation who had
breast cancer and a subsequent oophorectomy was 0.38
(95% CI, 0.19-0.077; P =
.007).
Data source: The retrospective
cohort study evaluated 676
women with BRCA1 or BRCA2
mutations and breast cancer diagnosed from 1975 to
2008.
Disclosures: Dr. Kelly Metcalfe
reported having no disclosures.
The research was funded by
the Canadian Breast Cancer
Foundation.
BY JENNIFER KELLY SHEPPHIRD
FR O M J A M A O N C O LO G Y
W
omen with breast cancer
and BRCA1 mutations had
a lower risk of mortality if
they underwent oophorectomy, and the
benefit was apparent beyond age 50,
investigators reported online April 23 in
JAMA Oncology.
In the entire cohort that included
women with BRCA1 and BRCA2 mutations, breast cancer–related mortality
was reduced 56%, and all-cause mortality (including 9 deaths due to ovarian
cancer) was reduced 65% with oophorectomy (adjusted HR, 0.35; 95% CI,
0.22-0.56; P < .001).
Dr. Kelly Metcalfe of the Women’s
College Research Institute, Toronto, and
her colleagues provided evidence in support of BRCA1 testing in women with
early-stage breast cancer at the time of
diagnosis.
“The data presented here suggest that
oophorectomy should be discussed with
the patient [with a BRCA1 mutation]
shortly after diagnosis. We recommend
that the operation be performed in the
first year of treatment to maximize the
benefit,” the investigators wrote ( JAMA
Oncol. 2015 Apr. 23 [doi:10.1001/jamaoncol.2015.0658]).
The historical cohort study evaluated
676 women with BRCA1 or BRCA2
mutations and early-stage breast cancer
diagnosed between 1975 and 2008. In order to examine the impact of subsequent
oophorectomy on mortality risk due to
breast cancer, a requirement for inclusion
was that both ovaries be intact at the
time of diagnosis. The subsequent oophorectomy group included 345 women.
Among the women who underwent
oophorectomy, women with a BRCA1
mutation had a significantly reduced
risk of breast cancer–related death, but
the association was not significant for
those with BRCA2 mutations. However, the number of BRCA2 carriers
was much smaller than the number of
BRCA1 carriers, and the 95% CI range
was wide (0.23-1.43). A larger sample is
required to determine the strength of
an association.
Regardless of BRCA1/2 mutation status, in patients with estrogen receptor–
negative breast cancer, oophorectomy
had a protective effect (HR, 0.07; 95%
CI, 0.01-0.51; P = .009).
Among 14 women over age 50 with
estrogen receptor–negative cancer who
did not undergo oophorectomy, 3 (21%)
died; of the 15 who underwent the surgery, none died. Based on this finding,
and a previous study indicating a protective effect of oophorectomy on the risk
of primary breast cancer in women over
50, the researchers concluded that “the
postmenopausal ovary remains active in
terms of androgen production and that
this affects cancer risk and progression,
either directly or through aromatization
to estrogen.”
[email protected]
Digital Weekly Summaries of
Must-Read Clinical Literature,
Guidelines, and FDA Actions
Guideline Update: VTE Prophylaxis
and Treatment in Oncology
What to use for venous thromboembolism in
cancer patients
A
n American Society of Clinical Oncology update to
the Clinical Practice Guideline for the prophylaxis and
treatment of venous thromboembolism (VTE) in patients
with cancer includes the following:
• Thromboprophylaxis is generally required during
hospitalization for patients with active cancer, but it is not
recommended for outpatient treatment except in selected
high-risk patients.
• Patients with multiple myeloma receiving antiangiogenesis
agents with chemotherapy and/or dexamethasone should
receive prophylaxis with either low-molecular weight heparin
(LMWH) or low-dose aspirin.
• Patients who are undergoing major surgery should receive
prophylaxis starting before surgery and continue for at
least 7 to 10 days; up to 4 weeks in those undergoing major
abdominal or pelvic surgery with high-risk features.
• LMWH is recommended for the first 5 to 10 days of treatment
for deep vein thrombosis or pulmonary embolism and for
long-term secondary prevention of at least 6 months.
• Novel oral anticoagulants are not recommended for patients
with malignancy and VTE at this time.
• Anticoagulation should not be used to extend survival of
patients with cancer in the absence of other indications.
• Patients should be periodically assessed for VTE risk and
educated about the signs and symptoms of VTE.
CITATION: Lyman GH, Bohlke K, Khorana AA, et al. Venous
thromboembolism prophylaxis and treatment in patients with
cancer: American Society of Clinical Oncology clinical practice
guideline update 2014. J Clin Oncol. 2015. pii: JCO.2014.59.7351.
MRI Use in Multiple Myeloma
painful lesions, and distinguishing benign versus malignant
osteoporotic vertebral fractions
• detects spinal cord or nerve compression and soft tissue masses
IMWG’s recommendations for use of MRI include:
• the workup of solitary bone plasmacytoma
• whole-body MRI for all patients, or spine and pelvic MRI
when whole-body scan is unavailable
• patients with 1 or more focal lesion greater than 5 mm should
be considered symptomatic and receive therapy
• in cases with equivocal small lesions, a second MRI should
be performed after 3 to 6 months; if progression is detected,
treat as symptomatic
CITATION: Dimopoulos MA, Hillengass J, Usmani S, et al. Role
of magnetic resonance imaging in the management of patients
with multiple myeloma: a consensus statement. J Clin Oncol.
2015;33(6):657-664. doi: 10.1200/JCO.2014.57.9961.
These are just two examples of what you’ll find at
ClinicalEdge Oncology. New summaries are
posted each week. Read more at
www.oncologypractice.com/clinicaledge
O N C O L O G Y
ClinicalEdge Oncology is what you, the busy
oncologist, have asked for—up to 5 succinct
summaries (like the ones on this page) of “mustread” news and clinical content.
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“Easy advance” scrolling and navigation features
Consensus Statement from the International
Myeloma Working Group
ClinicalEdge Oncology is updated weekly at
www.oncologypractice/clinicaledge
he International Myeloma Working Group (IMWG)
released a new consensus statement for the use of
magnetic resonance imaging (MRI) in multiple myeloma.
Reasons to support the use of MRI include:
• earlier detection of bone involvement
• high sensitivity for early detection of myeloma cells
infiltrating marrow
• gold standard for axial skeleton imaging, evaluating
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32
May 2015 • The Oncology Report
PD-L1 blockade breaks through triplenegative breast cancer
VITALS
Key clinical point: The investigative anti-PD-L1 immunotherapy MPDL3280A was
clinically active and generally
well tolerated in metastatic triple-negative breast cancer.
Major finding: The objective
response rate was 19% and
24-week progression-free survival 27%.
Data source: Phase Ia trial in
54 women with metastatic triple-negative breast cancer.
BREAST CANCER
Disclosures: Genentech/Roche
sponsored the study. Dr.
Emens reported consulting
for Vaccinex, Celgene, Aveo,
Bristol-Myers Squibb, and research/grant support from Genentech, Roche, EMD Serono,
MaxCyte, Amplimmune, and
Merck. Dr. Emens and her institution also receive payments
and royalty on a breast cancer
vaccine.
BY PATRICE WENDLING
FR O M TH E A A C R A N N U A L M E E TI N G
M
etastatic triple-negative breast
cancer appears to be the latest
hard-to-treat cancer to yield to
the juggernaut that is now anti-PD-L1
immunotherapy.
MPDL3280L, an investigational
monoclonal antibody against programmed death ligand 1 (PD-L1),
posted an overall response rate of 19%
among 21 evaluable patients in a phase
Ia trial (95% confidence interval, 5-42).
This included two complete responses
in patients with high PD-L1 expression
and two partial responses. Three of the
four responses are ongoing, Dr. Leisha
Emens reported at the annual meeting
of the American Association for Cancer
Research.
“I think it very well could be the first
targeted therapy that bears out in a larger trial,” she said during a press briefing.
“These data are still early, and we need
to enroll and treat a lot more patients
with this agent, but I think it has great,
great promise for this particular breast
cancer subtype.”
There is great unmet need for new
treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes
do, and the only approved treatment
option in the United States is chemotherapy.
TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted
therapies, because it has a higher mutation rate than do other breast cancer
subtypes. This produces neoantigens
that can be recognized as foreign by the
immune system and be more effective
targets for an immune response,Dr.
Emens of the Johns Hopkins Sidney
Kimmel Comprehensive Cancer Center,
Baltimore, explained.
TNBC also has higher PD-L1 expression levels, which can inhibit T-cell
antitumor responses, and more tumor-infiltrating lymphocytes, which can
facilitate a immune response and are associated with improved outcomes when
present in high numbers.
MPDL3280A is designed to inhibit the
binding of PD-L1 to programmed death
receptor 1 (PD-1) and B7.1, which can
restore antitumor T-cell activity and enhance T-cell priming, she said.
The checkpoint inhibitor received
breakthrough therapy designation for
metastatic bladder cancer in 2014 and
a second designation in non–small cell
lung cancer in February.
The ongoing phase Ia trial enrolled
54 women with metastatic TNBC and
an ECOG performance status of 0 or
1. This included 21 patients initially selected for high PD-L1 expression levels
(at least 5%) on their immune cells and
33 all-comers. MPDL3280A intravenous
infusions were given every 3 weeks at
doses of 15 mg/kg, 20 mg/kg, or 1,200
mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.
At 24 weeks, progression-free survival
was 27% (95% CI, 7-47), Dr. Emens said.
The median duration of response
(range, 18-56+ weeks) has not been
reached.
Three patients with progressive disease experienced pseudoprogression,
where the target lesion shrank, but new
lesions developed. Pseudoprogression,
a feature of checkpoint inhibition that
also has been seen with ipilimumab
(Yervoy), is new for many physicians to
manage and requires the patient’s entire
clinical picture be taken into account,
Dr. Emens said.
“An important component of the phenomenon of pseudoprogression is that
if you see evidence of new lesions on
a scan and the patient’s doing clinically
well, you continue to treat and then
reevaluate subsequent to that,” she said.
“If there’s progression at that point,
then potentially you consider changing
the therapy or just following the patient
more closely. Another potential option
to help sort through that is to try and
obtain tissue from one of those lesions
oncologyreport.com33
Center, commented that it wasn’t that
long ago that phase I investigators
were pleased if they saw even a hint
of activity that would justify moving
forward to phase II. The activity signals with the checkpoint inhibitors,
however, are “unequivocal” and the
implications for the future treatment
of people with triple negative breast
cancer are “very, very exciting,” according to Dr. Winer.
Earlier in the meeting, stellar results
with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial
upended the treatment paradigm for
advanced melanoma. Pembrolizumab
has been evaluated in TNBC and the
safety profile and responses are similar
to those with MPDL3280A, Dr. Emens
said.
A global phase III trial evaluating MPDL3280A in combination with paclitaxel
(Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.
DR. LEISHA EMENS
“
These data
are still early,
and we need
to enroll and
treat a lot more
patients with
this agent, but
I think it has
great, great
promise for
this particular
breast cancer
subtype.
[email protected]
On Twitter @pwendl
BREAST CANCER
©Brian C hase /Thinkstock.com
to get some idea of what is happening,
if it’s a phenomenon of the inflammatory response or a response to the
therapy.”
Dr. Emens detailed one such case in
which three target lesions decreased in
size from baseline on 9- and 20-month
follow-up scans, but newly enlarged axillary nodes that appeared inflammatory
or necrotic developed near the third
target lesion at 9 months. The patient
remained on therapy and is doing well
today, with further shrinkage of the target lesion and regression of the axillary
nodes at 20 months.
MPDL3280A was generally well
tolerated, with fatigue, nausea, fever,
decreased appetite, and asthenia being
the most common adverse events, Dr.
Emens said. In all, 11% of patients
experienced grade 3 treatment-related
events. Two deaths, assessed as drug
related by the investigator, are under
investigation.
Press briefing moderator Louis M.
Winer, director of the Georgetown
Lombardi Comprehensive Cancer
34
May 2015 • The Oncology Report
FDA panel backs T-VEC for advanced
melanoma, with precautions
BY ELIZABETH MECHCATIE
AT AN FD A A D V I S O RY C O MMI TTE E M E E TI N G
“
MELANOMA
What’s very,
very clear
is there is a
response of
the injected
lesions,” and
local control
of lesions is
important to
patients.
SILVER SPRING, MD. – A Food and
Drug Administration advisory panel
supports approval of talimogene laherparepvec (T-VEC), an oncolytic immunotherapy, voting 22-1 that the overall
risk-benefit profile is favorable for treatment of patients with injectable regionally or distantly metastatic melanoma.
At a joint meeting of the FDA’s Oncologic Drugs Advisory Committee and
the Cellular, Tissue and Gene Therapies
Advisory Committee on April 29, panelists agreed that it was clear that at least
some subpopulations of patients can
benefit from this treatment, but cautioned that while nonvisceral metastases
may respond to treatment, it was not
clear whether visceral metastases responded, and that it should not be used
to treat visceral disease. They also recommended that labeling should discourage clinicians from using this treatment
in patients with substantial metastatic
disease.
T-VEC is a first-in-class oncolytic
immunotherapy derived from herpes
simplex virus type 1 (HSV-1) the virus
that causes most cold sores. It has been
genetically modified to attenuate its virulence and engineered to express granulocyte-macrophage colony-stimulating
factor (GM-CSF), while remaining susceptible to antiviral treatments such as
acyclovir. T-VEC is injected directly into
cutaneous, subcutaneous, or nodal lesions, “resulting in selective lysis of the
injected tumor cells (and not normal
tissue),” which “results in the release
and presentation of tumor-derived antigens and local expression of GM-CSF to
initiate a systemic anti-tumor immune
response that also induces regression
of non-injected and distant lesions,”
according to the Amgen briefing documents. If approved, this would be the
first virus-based cancer treatment, the
company noted.
The FDA panel looked at a phase III,
open-label, multicenter randomized
study that compared treatment with
T-VEC to GM-CSF (administered subcutaneously) in 436 people with melanoma (stage IIIB/C or stage IV with
limited visceral disease burden that was
considered unresectable); the trial began
before several targeted and biologic
treatments that are now available for
advanced melanoma were approved.
About half the patients had been treated previously for melanoma and more
than 20% were older than 75 years; 292
patients were treated with T-VEC (up to
4 mL injected into one or more subcutaneous or nodal melanoma lesions every
1 or 2 weeks until clinically relevant
disease progression occurred or there
was no more residual tumor to inject)
and 141 received GM-CSF daily in the
control arm (for 14 days and off for 14
days).
The primary efficacy endpoint was
the durable response rate (DRR), defined as the proportion of patients
with responses (complete or partial)
“maintained continuously for 6 or more
months and beginning at any point
within 12 months of initiating therapy,”
as assessed by a blinded independent
committee. That endpoint was met by
16.3% of those treated with T-VEC vs.
2.1% of those on GM-CSF, a significant
difference (P < .0001).
Other results included the overall
response rate – complete or partial –
which was 26.4% in the T-VEC group
vs. 5.7% in the control group; Complete
response was 10.8% among those on
T-VEC, vs. 0.7% among those on GMCSF.
Among the approximately 400 patients treated with T-VEC in this and
five other studies, the most common adverse events were expected, namely, cellulitis and flu-like symptoms, and most
adverse events were mild or moderate.
Disease progression and cellulitis
were the most common serious adverse
events and occurred more often among
those on T-VEC (3.1% vs. 1.6%, and
oncologyreport.com35
2.4% vs. 0.8%, respectively). Fatal adverse events were higher among those
on T-VEC (3.4% vs. 1.6%); disease
progression was the most commonly
reported.
Almost 6% of those on T-VEC reported herpetic events, mostly oral
herpes, but there were no serious herpes complications or cases of secondary transmission. Amgen has proposed
a risk management plan to address the
risks of the treatment, including herpetic lesions, accidental exposures to
health care professionals, and secondary transmission, and postmarketing
studies.
Several panelists pointed out that
the company‘s claims that T-VEC has
a systemic effect was not necessarily
substantiated by the data, and that the
unresectable disease qualifier should be
added to the indication. Other points
made by panel members were that the
dosing instructions were not sufficient,
and that while the safety profile was
acceptable, the risks of cellulitis and of
shedding on family members, pregnant
women, children, health care professionals, and other cancer patients were
concerns. Panelists also noted that it is
unclear how T-VEC compares to the
other treatments that have been approved for advanced melanoma over the
past several years.
“What’s very, very clear is there is a
response of the injected lesions,” and
local control of lesions is important to
patients, said panelist Dr. Patrick Hwu,
professor in the department of melanoma medical oncology, University
of Texas M.D. Anderson Cancer Center, Houston. Based on the data, “this
clearly ... will be among the least toxic
agents for cancer given in the [melanoma] clinic,” compared to other treatments, he added.
The FDA usually follows advisory
panels’ recommendations. An FDA decision on approval is expected by Oct. 27,
2015, according to Amgen. Panelists had
no potential conflicts of interest related
to this meeting.
If approved,
this would be
the first virusbased cancer
treatment,
the company
noted.
[email protected]
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MELANOMA
36
May 2015 • The Oncology Report
Immunotherapy-related toxicities are
varied, early diagnosis is key
“
MELANOMA
The key to
successful
management
of checkpoint
protein
antibody
toxicities is
early diagnosis,
high suspicion,
excellent
patient-provider
communication,
and rapid and
aggressive
use of
corticosteroids
and other
immune
suppressants
for immunerelated AEs.
BY JENNIFER KELLY SHEPPHIRD
FROM J O U R N A L O F C LI N I C A L O N C O LO G Y
T
oxicities associated with immunotherapies cover a wide range
from capillary leakage with
cytokine therapies, to damaging cross
reactivities of cell therapies, to autoinflammatory reactions observed with immune checkpoint inhibitors, according
to a review published online April 27 in
the Journal of Clinical Oncology.
Most toxicities involve hyperactivated
T-cell responses directed against healthy
tissue. In general, cytokine therapy
generates diffuse, nonspecific T-cell
reactivity, while vaccines, adoptive cell
therapy, and checkpoint protein inhibitors generate specific T-cell responses
directed to normal tissue that can cause
organ damage.
Dr. Jeffrey S. Weber, director of the
Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt
Cancer Center and Research Institute,
Tampa, and his colleagues summarized
the toxicities specific to immunotherapies and emphasized the importance of
oncology practitioners understanding
the spectrum of adverse events and
treatment options available ( J. Clin.
Oncol. 2015 Apr. 27 [doi:10.1200/
JCO.2014.60.0379]).
Minimal toxicity has been observed
with cancer vaccines, possibly because
the tumor-associated targets are overexpressed in cancer cells but are found
at low or undetectable levels in normal
cells. Human epidermal growth factor
receptor 2 (HER2), p53, and survivin are
the most common vaccine targets. Sipuleucel-T, the one currently approved
vaccine, has a favorable toxicity profile,
with transient chills, fatigue, and fever
the most common adverse events (AEs).
By contrast, cytokines are associated
with frequent and severe AEs, which
has dampened enthusiasm for the treatment. The FDA approved recombinant
human interferon-alpha (IFN) for the
treatment of hairy cell leukemia and
high-risk melanoma, and interleukin-2
was approved for advanced renal cell
carcinoma and melanoma.
IFN treatment results in constitutional symptoms of fever and fatigue
in more than 80% of recipients, as well
as headache and myalgia. Nonsteroidal
anti-inflammatory drugs are helpful. Up
to one-third of patients have diarrhea
and two thirds have nausea and anorexia. Neuropsychiatric issues are observed,
such as confusion in about 10% of
patients, depression in up to 45%, and
psychosis in less than 1%. Prophylactic
antidepressants may reduce the risk of
depression in those with a history of
depression, but careful monitoring of all
patients is suggested.
Thrombocytopenia and leukopenia
are observed in up to 10% of patients.
Hyperthyroidism or hypothyroidism occurs in 10%-15% of patients. Sarcoid is
rare, but may be confused with disease
progression in patients with melanoma
or lymphoma. IFN may cause autoimmune events, but some investigators
noted that this may be associated with
improved treatment outcomes.
IL-2 treatment leads to increased vascular permeability and fluid retention,
including pleural effusions and pulmonary edema, hypotension, and prerenal
azotemia. Thrombocytopenia, anemia,
coagulopathy, or neutrophil chemotaxis
impairment leading to catheter infections may occur. Neurotoxicity associated with IL-2 can be subtle, such as
lethargy and irritability, or severe as in
florid psychosis.
Mediators of IL-2 toxicity include nitric
oxide, IL-1, tumor necrosis factor–alpha,
and IFN-gamma, but inhibitors of these
toxic factors have been unsuccessful.
Adoptive T-cell therapies have effectively treated patients with certain metastatic cancers, including melanoma,
metastatic cervical cancer, and B-cell
malignancies. Preparative chemotherapy for lymphodepletion leaves patients
at risk for sepsis and bleeding before
hematopoietic recovery, which is the
oncologyreport.com37
dominant cause of a 1%-2% rate of
mortality.
Cytokine release syndrome resembles
sepsis and is also seen with high-dose
IL-2. With supportive care, even severe
renal failure, coma, and respiratory
failure are completely reversed usually.
IL-6 was identified as a mediator in one
case involving B-cell malignancy, and an
IL-6 receptor-blocking antibody showed
apparent benefit.
Autoimmunity induced by the T cells
may occur, the consequences of which depend on the level and distribution of the
normal tissue expression of the target.
Standard interventions for life-threatening adverse responses to T-cell therapy include high-dose corticosteroids
and alemtuzumab (anti-CD52 antibody)
to suppress lymphocytes, a treatment
which may circumvent antitumor effects as well.
Since 2011, checkpoint inhibitors ipilimumab (anti-CTLA-4), pembrolizumab,
and nivolumab (both anti-PD-1) have
been approved by the Food and Drug
Administration and are commonly used
for patients with melanoma and other
cancers. Autoimmune reactions are
common, and all patients are recommended to have thyroid function studies, complete blood counts, and liver
function and metabolic panels at each
treatment and regular intervals for 6
T
The
months following treatment.
Ipilimumab toxicities are dose related,
while toxicities associated with PD-1
blockade do not appear to be dose related. The most common drug related
AEs of any grade were fatigue, pruritus,
and rash.
Toxicities associated with PD-1 antibodies vary depending on the histology
treated. For severe colitis caused by ipilimumab or PD-1 antibodies, high doses
of corticosteroids are required, and infliximab administered in patients whose
colitis fails to resolve within three days.
The onset of immune-related AEs follows a predictable pattern, with skin-related toxicities occurring first, followed
by colitis, then hepatitis and endocrinopathies observed between weeks 12
and 24.
“The key to successful management
of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication,
and rapid and aggressive use of corticosteroids and other immune suppressants
for immune-related AEs,” Dr. Weber
and his associates wrote.
Dr. Weber and his associates reported receiving research funding from or
having consulting or advisory roles with
several industry sources.
Oncology
Report
80%
of recipients
had
constitutional
symptoms
of fever and
fatigue, as well
as headache
and myalgia,
from IFN
treatments.
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BREAST CANCER
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Hope S. Rugo, M.D.
University of California,
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MELANOMA AND SKIN CANCERS
Jeffrey A. Sosman, M.D.
Vanderbilt University
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PATIENT AND SURVIVORSHIP CARE
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Mayo Clinic Cancer Center
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George D. Demetri, M.D.
Harvard Medical School
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OncologyReport.com • The Oncology Report • May 2015 • Volume 11 • Number 5
Editor in Chief Mary Jo M. Dales
Executive Editors Denise Fulton, Kathy Scarbeck
Editor Laura Nikolaides
Senior Editors Therese Borden, Jeff Evans, Catherine Hackett, Gina L.
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