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PERSPECTIVES FROM
July 25, 2016
ASCO Annual Meeting
A HemOnc Today Special Report
Chemoradiation improves OS, PFS in
older patients with glioblastoma
Patients with MGMT–methylated tumors experienced
greatest benefit
Pembrolizumab improves long-term
outcomes in advanced melanoma
Patients derived benefit regardless of prior
treatment with ipilimumab
Trastuzumab biosimilar safe, effective
for advanced breast cancer
Biosimilar has potential as “affordable treatment
option” for HER-2–positive breast cancer
Chimeric antigen receptor T cells
exhibit efficacy in advanced lymphoma
Anti–CD19 CAR T cells may become “important part
of lymphoma therapy”
This HemOnc Today supplement is produced by SLACK Incorporated.
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ASCO Annual Meeting highlights
head1
late-breaking clinical trials,
research updates
Originally published in HemOnc Today | Date TBD, 2016
TARGETING CANCER STEM CELL
PATHWAYS AND STEMNESS
Not all cells within a tumor are equal
Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new
approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are
highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid
and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2
The CSC model may help explain tumor recurrence
The CSC model is a radical departure from the clonal evolution
model. In the clonal evolution model, all cells within a malignant
tumor have similar tumorigenic activity.5 By contrast, in the CSC
model only a subset of tumor cells, CSCs, have tumor-initiating
capability.2 Cancers are organized in a cellular hierarchy,
with the CSCs at their apex having tumor-initiating capability.5
One important clinical implication of the CSC model is that it
may help to explain why early tumor shrinkage is often poorly
predictive of overall survival.6,7 While conventional therapies kill
the bulk of non-stem cancer cells, resulting in tumor shrinkage,
CSCs may remain viable and later reestablish the tumor,
leading to relapse.8 Tumors with increased expression of genes
associated with CSCs have also been correlated with lower
overall survival in breast and lung cancers.9
Stemness of CSCs may lead to tumorigenicity
The heterogeneous high tumorigenicity of CSCs may be a direct
result of their stemness. In both normal stem cells and CSCs,
stemness is defined by the characteristics of self-renewal and
differentiation.8 Unlike normal stem cells, which differentiate
into healthy, mature, cell types, CSCs differentiate into cancer
cells. The stemness of CSCs is maintained by several signaling
pathways that are overexpressed and overactivated, including
JAK-STAT, Wnt/β-catenin, Hedgehog, Nanog, Notch, TGF-β,
Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways
maintain stemness and promote tumorigenicity. This makes
CSCs phenotypically different from non-stem cancer cells and
confers therapy resistance.4
References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A.
2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives.
World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic
cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S,
ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer.
wClin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line
therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate
endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):13411347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic
role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the
therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid
tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation
in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell
Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S.
Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A,
Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification
of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat
Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679.
20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844.
21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting
stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.
EDU-NPS-0108 6/2016 ©2016 Boston Biomedical
Epithelial-mesenchymal transition (EMT)
of CSCs may lead to metastasis
CSCs are also able to transform to a mesenchymal state by the
process of EMT. In this state, CSCs become highly migratory and
invasive and therefore prone to metastasis.13,15 After spreading
to a distant site, they can undergo mesenchymal-epithelial
transition and become tumorigenic, colonizing the new site.15
This is a potential mechanism for how CSCs contribute to
metastasis and recurrence. Some evidence suggests that EMT
and stemness may be coupled, as they are mediated by many of
the same factors.16
T
he ASCO Annual Meeting, held in Chicago from
June 3-7 under the theme “Collective wisdom: The
future of patient-centered care and research,” brought
together hematologists and oncologists from around the
world for 5 days of late-breaking clinical trials and research updates.
Key areas of focus included breast cancer, glioblastoma
and melanoma. Numerous presentations also demonstrated the benefits of immunotherapy in multiple cancer
subtypes. An address by Vice President Joe Biden on the
Web watch
CSCs are highly resistant to conventional
cancer therapies
Although current chemotherapies and radiotherapy can kill
most non-stem cancer cells, CSCs remain highly resistant.17,18
Further, conventional therapies have been shown to increase
the percentage of CSCs within malignant residual tumors.19,20
Many mechanisms that mediate the therapy resistance
of CSCs have been identified, including overactivated
stemness signaling.10
A key implication of the CSC model for cancer treatment is
that both CSCs and non-stem cancer cells should be targeted
to reduce tumor recurrence and metastasis.19,21 Several
approaches to targeting CSCs are being studied, including
stemness-associated signaling pathways that may mediate
tumorigenesis, metastasis, and resistance.1,22 The next
generation of cancer therapeutics is in development with
investigational agents designed to inhibit stemness pathways.1
national cancer moonshot initiative focused on collaboration and “a lot more openness” among clinicians and researchers.
This HemOnc Today supplement provides readers with
an overview of the most noteworthy – and potentially practice-changing – findings presented at the ASCO Annual
Meeting. Perspectives from physicians in the hematology/
oncology communities provide further insight into the impact these findings may have in everyday practice.
— The Publishers of HemOnc Today
Video Coverage
Visit Healio.com/Hematology-Oncology for more
in-depth coverage of the findings in immuno-oncology
presented at the meeting in the Discoveries from ASCO:
Immuno-oncology resource center. The resource center
provides exclusive video perspectives from key opinion
leaders regarding late-breaking clinical trials and other
recent research in immuno-oncology to be presented at
the ASCO Annual Meeting.
Visit Healio.com/Hematology-Oncology to hear more from
Brian Bolwell, MD, chairman of the Taussig Cancer Institute
at Cleveland Clinic, about studies on the affordability of higher,
escalating drug prices for cancer treatments in the United States
and other countries.
“Figuring out how to work
with pharma to try to
moderate … drug pricing is
utterly imperative both for
the health care economy,
as well as for our citizens.”
— BRIAN BOLWELL, MD
Learn more at www.bostonbiomedical.com
Boston Biomedical is developing the next generation of cancer therapeutics
with drugs designed to inhibit cancer stemness pathways. Clinical trials are
underway with the goal of reducing recurrence and metastasis.
© Copyright 2016, SLACK Incorporated. All rights reserved. No part of this publication may be reproduced without written permission. The ideas and opinions expressed in this HemOnc Today® supplement do
not necessarily reflect those of the editor, the editorial board or the publisher, and in no way imply endorsement by the editor, the editorial board or the publisher.
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This HemOnc Today supplement is produced by SLACK Incorporated.
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| July 25, 2016 | Healio.com/HemOnc
Originally published in HemOnc Today | June 25, 2016
Originally published in HemOnc Today | July 10, 2016
Chemoradiation improves OS, PFS in older
patients with glioblastoma
Age, complications influence death after
colon cancer surgery
T
he addition of concomitant and
adjuvant temozolomide to hyperfractionated radiation therapy significantly prolonged PFS and OS among
older patients with newly diagnosed
glioblastoma, according to phase 3 study
results presented during the plenary session of the ASCO Annual Meeting.
Patients with MGMT–methylated
tumors derived the greatest benefit
from temozolomide.
Although glioblastoma occurs primarily in older adults, no clear guidelines for treatment have been defined.
“The peak age of incidence of glioblastoma is 64 years, and the incidence
appears to be increasing with our aging population,” James R. Perry, MD,
FRCPC, Crolla family endowed chair
in brain tumor research at Odette Cancer Centre and Sunnybrook Health Sciences Centre in Toronto, said during a
press conference. “The current best
practice is surgical resection, followed
by radiotherapy combined with chemotherapy.”
A trial conducted by the EORTC
suggested a survival benefit could be
gained through the addition of temozolomide to radiation therapy in newly
diagnosed patients; however, the researchers observed a trend of decreasing benefit with increasing age, and the
potential OS benefit of the combination in older patients remained unknown.
“The studies that we have in older patients over 65 years have only compared
radiation schedules head-to-head,
or radiation alone vs. temozolomide
alone,” Perry said. “There has never
been a trial of combined chemotherapy
with radiation in elderly patients.”
Perry and colleagues conducted a
global randomized clinical trial of 562
older patients (median age, 73 years;
range, 65-90; 61% men).
Researchers randomly assigned
patients to 40 Gy radiation therapy
in 15 fractions, with or without 3
weeks of concomitant temozolomide
and monthly adjuvant temozolomide
(n = 281 for both). Patients assigned
adjuvant temozolomide received treatment for up to 12 cycles or until progression.
Patients assigned temozolomide
achieved longer median OS (9.3
months vs. 7.6 months; HR = 0.67;
95% CI, 0.56-0.8) and longer median PFS (5.3 months vs. 3.9 months;
HR = 0.5; 95% CI, 0.41-0.6) than those
assigned radiation alone.
A total of 462 patients provided an
adequate tissue sample for MGMT
analysis, which has been conducted in
354 patients to date.
P
erioperative complications increased the 1-year risk for death
after colon cancer surgery among
patients of all ages, according to study
results.
The elevated risk extended beyond
the 30-day postoperative period, and
nearly one-quarter of patients aged
older than 65 years died of cardiovascular disease.
tients by age group — younger than 65
years, 65 years to 74 years, and 75 years
or older — and by occurrence of major
complications. They then compared
age groups with cause of death 1 year
after surgery.
Overall, 3.3% of patients died within 30 days of surgery, and 11.6% died
within 1 year. Mortality varied by age
group (< 65 years, 3.8%; 65-74 years,
Chemoradiation continues on page 7
PERSPECTIVE
The take-home message of this trial is that, regardless of the
age of the adult patient, it is now becoming the standard of
care to give radiotherapy plus temozolomide to patients
with newly diagnosed glioblastoma. The second important
takeaway is that the benefit of temozolomide was most pronounced among those with glioblastomas that demonstrated
methylation of the promoter for a gene called MGMT. However, there also was a benefit regardless of MGMT methylation.
The context for why this is important is twofold. One, the
prior practice-changing trial that led to our current standard
of care of radiotherapy and temozolomide in patients with
glioblastoma excluded patients aged older than 70 years. In addition, that prior trial
suggested the benefit of temozolomide decreased with age. Therefore, it was unclear whether temozolomide prolonged survival when combined with radiotherapy
in patients aged older than 70 years.
Andrew B. Lassman
The other important aspect of this study was the length of the radiotherapy course.
In this trial it was 3 weeks, whereas it was 6 weeks in the prior landmark trial by Stupp
and colleagues. Six weeks of radiotherapy can be a rough treatment in older patients,
and there had been previous studies demonstrating that a shortened course, using
a technique called hypofractionation, was not inferior to a 6-week course in older
patients.
What remains unclear is whether radiotherapy itself can be omitted in elderly patients with MGMT–methylated tumors. This trial included two arms, both of which
had radiation. The question was whether adding temozolomide to radiation was
beneficial, and the answer was yes. The flip question of randomly assigning patients
to get temozolomide alone or with radiotherapy remains unanswered.
References:
Roa W, et al. J Clin Oncol. 2004;doi:10.1200/JCO.2004.06.082.
Stupp R, et al. N Engl J Med. 2005;10;352:987-996.
— Andrew B. Lassman, MD
NewYork-Presbyterian
Columbia University Medical Center
Disclosure: Lassman reports no relevant financial disclosures.
“Traditionally, there has not been as much focus
placed on the management of the patient’s other
comorbidities, which may be driving the higher rates
of death from cardiovascular disease.”
— Christopher Thomas Aquina, MD, MPH
Few studies have focused on age-related differences in the rate and cause
of death beyond the postoperative period among patients undergoing colectomy.
“Most of the previous studies looking at long-term outcomes have focused on oncologic endpoints, such
as RFS, to analyze the effects of different treatment regimens,” Christopher
Thomas Aquina, MD, MPH, surgical resident at University of Rochester
Medical Center and research fellow
at Surgical Health Outcomes & Research Enterprise, told HemOnc Today. “This research has been critical in
improving outcomes for patients, but
it has not traditionally accounted for
other factors influencing OS.”
Aquina and colleagues accessed
the New York State Cancer Registry
and Statewide Planning and Research
Cooperative System to identify 26,420
patients who underwent colectomy for
stage I to stage III colon adenocarcinoma between 2004 and 2011.
The researchers categorized pa-
8.3%; ≥ 75 years, 18.8%).
A greater percentage of older patients experienced a major complication (< 65 years, 23.3%; 65-74 years,
29.9%; ≥ 75 years, 38.2%). Postop-
erative complications significantly
increased the risk for death at 1 year
across all age groups: aged older than
65 years (6.4% vs. 1.9%); 65 to 74 years
(12.8% vs. 3.8%); 75 years or older
(22.4% vs. 9.2%; P < .0001 for all).
Although colon cancer was the
leading cause of death in all cohorts, a
greater proportion of younger patients
died of the disease than older patients
(< 65 years, 58%; ≥ 75 years, 43.9%).
However, the risk for death caused
by cardiovascular disease increased
with age. More than one-quarter
(27.8%; n = 429) of patients aged 75
years or older died of cardiovascular
disease, compared with 9.3% (n = 21)
of patients aged younger than 65 years
and 20.7% (n = 83) of patients aged 65
years to 74 years.
“The major focus following surgery typically involves preventing
cancer recurrence through close onAge continues on page 7
PERSPECTIVE
This study adds to the landscape of knowledge in terms of
postoperative outcomes in older adults who undergo surgery for colon cancer. This study highlights the importance
of integrating geriatric oncology practices. As patients aged,
the overall risk for postoperative complications increased, resulting in higher rates of 1-year mortality.
Two individuals with the same chronological age do not necessarily have the same functional or physiological age. The
study of the use of geriatric oncology principles, such as a
Daneng Li
comprehensive geriatric assessment, is already underway
in terms of preoperative assessment for older adults getting ready for surgery. This
is important because doctors can identify potential vulnerabilities that a surgeon
might not be able to anticipate through a standard history or physical exam. As a
result of that, we can research potential interventions for vulnerabilities detected
through the geriatric assessment to improve overall surgical outcomes.
This study identifies age as a risk factor for long-term mortality, and it really emphasizes the need for geriatric oncology principles and comprehensive geriatric assessment in the preoperative and perioperative settings.
— Daneng Li, MD
City of Hope
Disclosure: Li reports no relevant financial disclosures.
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| July 25, 2016 | Healio.com/HemOnc
| July 25, 2016 | Healio.com/HemOnc
7
Originally published in HemOnc Today | June 25, 2016
Chimeric antigen receptor T cells exhibit
efficacy in advanced lymphoma
T
reatment with T cells genetically
modified to express chimeric antigen receptors that target CD19
induced remission in patients with
advanced B-cell lymphoma when administered with low-dose chemotherapy, according to study results.
The use of chimeric antigen
receptor (CAR) T cells may become
a standard of care for advanced lymphoma in the near future, according
to James N. Kochenderfer, MD, investigator in the experimental transplantation and immunology branch
of the NCI’s Center for Cancer Research.
“T cells that are genetically modified to express CARs targeting CD19
have significant activity against B-cell
malignancies,” Kochenderfer said
during his presentation. “In almost
all clinical trials of anti–CD19 CAR T
cells, the T-cell infusions are preceded
by chemotherapy, because depletion
of the recipient leukocytes has been
shown to enhance the activity of
adoptively transferred T cells.”
Kochenderfer and colleagues previously reported data from patients
treated with CAR T cells and highdose chemotherapy.
In the current analysis, researchers
assigned 22 patients with advanced
lymphoma to low-dose conditioning chemotherapy, followed by anti–
CD19 CAR T-cell infusion.
Nineteen patients had diffuse large
B-cell lymphoma (DLBCL). Two patients had follicular lymphoma and
one had mantle cell lymphoma.
Eighteen patients received daily cyclophosphamide (300 mg/m2
per day) for 3 days; the remaining four patients received a dose of
500 mg/m2 on the same schedule.
All patients received fludarabine
(30 mg/m2) on the same schedule.
Patients received a single dose of
CAR T cells 2 days after completion
of chemotherapy. After that, researchers analyzed blood CAR T cells and
serum cytokines.
The overall response rate for the entire cohort was 73%, with an ORR of
68% in the DLBCL patient population.
Eight patients with DLBCL
achieved complete response, as did
all patients with follicular lymphoma
and mantle cell lymphoma.
Five patients with DLBCL achieved
a partial response, with two patients
achieving stable disease. Four patients
PERSPECTIVE
This abstract provides additional data on chimeric antigen
receptor (CAR) T cells for the treatment of aggressive lymphomas. CAR T cells are very exciting, receiving much attention, and there are a lot of data coming out about their
use in lymphoid malignancies. One of the challenges is to
take them forward in a way that definitively demonstrates
their value compared with other treatments. This study included data from 22 patients and showed that a regimen
of fludarabine or cyclophosphamide in a nonmyeloablative
fashion, in addition to CAR T cells, could induce meaningful
John P. Leonard
remissions in patients with diffuse large B-cell lymphoma
(DLBCL). A few other aggressive subtypes were included, but most of the patients
in this report had DLBCL. A majority of patients in this study had a response. This is
exciting because it shows we can observe a high response rate when patients are
treated with CAR T cells. Further, the chemotherapy regimen used was attenuated
in dose, so we can attribute the effect primarily to the CAR T cells and less so to the
chemotherapy.
These additional data show this regimen has potential in the treatment of patients
with resistant, aggressive lymphoma. As far as follow-up is concerned, we need
additional studies with larger groups of patients, with longer follow-up periods, to
see if these responses are going to be durable. That is going to be quite important
to see in much larger patient populations. We also need to address the critical fact
that there is an inherent selection bias in CAR T-cell therapy. There are patients who
are not candidates for this type of treatment because of their age and comorbidity
burden, or because they have rapidly aggressive or growing disease. Because there
is an inherent delay of a few weeks required to get a patient enrolled and get them
CAR T cells — and sometimes longer to even be able to be considered for a spot
on a trial — some patients with aggressive lymphoma are left out because they
cannot wait that long for therapy. So, there is an inherent bias toward patients who
are healthy, and those who have more favorable (ie, less rapidly growing or symptomatic) disease, allowing them to wait a little longer for treatment.
That said, the lymphoma community remains excited, and it is safe to say there is a
good chance this treatment will be more widely used in the future.
— John P. Leonard, MD
Weill Cornell Medicine
NewYork-Presbyterian Hospital
Disclosure: Leonard reports a prior consultant role with Kite Pharma.
experienced progressive disease.
Ten patients’ responses remained
ongoing at the time of reporting, with
response durations ranging from 1
month to 20 months.
All but four patients had chemotherapy-refractory lymphoma or relapsed lymphoma after autologous
stem cell transplantation.
All patients developed fevers, and
55% (n = 12) experienced grade 3 or
grade 4 neurological toxicities. However, all toxicities resolved, typically
in less than 2 weeks, Kochenderfer
said.
Patients had a median CAR–positive cell level of 47 μL (range, 4-1,217).
Those who achieved complete or partial responses had higher peak blood
CAR–positive cell levels than those
with stable or progressive disease.
“Anti–CD19 CAR T cells are now
involved in multicenter trials,” Kochenderfer said. “They will probably become an important part of
lymphoma therapy in the future,
particularly to salvage the patients
who are refractory to chemotherapy
and have very few other options.”
– by Cameron Kelsall
n
Chemoradiation
reported more nausea, vomiting and
constipation than those assigned radiation alone.
The researchers reported high patient adherence to therapy, with more
than 97% of patients completing 3
weeks of chemoradiation.
“This is quite important, because
the elderly often have difficulties with
mobility, or with distance from treatment centers,” Perry said. “They sometimes don’t have a caregiver who is able
to bring them back and forth to treatment, so the shorter radiation schedule
is an advantage.”
Thirty-nine percent of patients assigned temozolomide and 41% of
patients assigned radiation alone re-
ceived systemic therapy after progression.
“Oncologists now have evidence to
consider radiotherapy with temozolomide in all newly diagnosed elderly
patients with glioblastoma,” Perry said.
– by Cameron Kelsall
n
bidity burden compared with younger
patients.”
Aquina told HemOnc Today that
he hopes these data will lead to stronger collaborations between surgeons
and medical oncologists.
“We hope that this work emphasizes the need for greater collaboration with our colleagues in geriatric
oncology to allow for a more nuanced
preoperative assessment, including a
comprehensive geriatric assessment
when appropriate,” Aquina said. “We
feel that multidisciplinary support
will help improve the delivery of care
to older patients with colon cancer.”
– by Cameron Kelsall
n
continued from page 4
Among the 165 patients with
MGMT–methylated tumors, those assigned temozolomide achieved longer
median OS than those assigned radiation alone (13.5 months vs. 7.7 months;
HR = 0.53; 95% CI, 0.38-0.73).
Unmethylated patients assigned
the combination had a median OS of
10 months, compared with 7.9 months
for those assigned radiation (HR =
0.75; 95% CI, 0.56-1.01).
A quality-of-life analysis showed no
differences in physical, cognitive, emotional or social functioning between
arms. Patients assigned temozolomide
Age
continued from page 5
cologic follow-up and appropriate use
of chemotherapy,” Aquina said. “Traditionally, there has not been as much
focus placed on the management
of the patient’s other comorbidities,
which may be driving the higher rates
of death from cardiovascular disease.
Older patients are more likely to have
higher rates of cardiovascular disease
and a higher overall level of comor-
Reference:
Kochenderfer J, et al. Abstract LBA3010.
Presented at: ASCO Annual Meeting; June 3-7,
2016; Chicago.
Disclosure: The NIH funded this study. Kochenderfer reports institutional research funding from Bluebird Bio and Kite Pharma, as well
as a patent agreement with Bluebird Bio. Please
see the abstract for a list of all other researchers’
relevant financial disclosures.
Reference:
Perry JR, et al. Abstract LBA2. Presented
at: ASCO Annual Meeting; June 3-7, 2016;
Chicago.
Disclosure: This study received funding from
the Canadian Cancer Society Research Institute, as well as from an unrestricted grant from
Schering-Plough/Merck. Perry reports stock
and ownership interests in DelMar Pharmaceuticals and VBL Therapeutics. Please see
the abstract for a list of all other researchers’
relevant financial disclosures.
Reference:
Aquina CT, et al. Abstract 10012. Presented
at: ASCO Annual Meeting; June 3-7, 2016;
Chicago.
Disclosure: Aquina reports no relevant financial disclosures. Other researchers report
consultant roles with Seattle Genetics and
UpToDate.
The CSC model may help explain tumor recurrence
TARGETING
CANCER STEM
CELL PATHWAYS
AND STEMNESS
Not all cells within a tumor are equal
Despite current advances in cancer therapy, tumor
recurrence and metastasis remain a clinical
challenge.1 A potential new approach to address this
is the targeting of a subset of the tumor cell population
known as cancer stem cells (CSCs). CSCs are highly
tumorigenic, unlike bulk tumor cells.2 Molecular
surface markers for CSCs have been demonstrated
within multiple solid and hematologic tumor types,
supporting the notion that not all cells within a tumor
are equal.3,4 This is the basis of the CSC model.2
The CSC model is a radical departure from the clonal
evolution model. In the clonal evolution model, all cells
within a malignant tumor have similar tumorigenic
activity.5 By contrast, in the CSC model only a subset
of tumor cells, CSCs, have tumor-initiating capability.2
Cancers are organized in a cellular hierarchy, with the
CSCs at their apex having tumor-initiating capability.5
One important clinical implication of the CSC model is
that it may help to explain why early tumor shrinkage
is often poorly predictive of overall survival.6,7 While
conventional therapies kill the bulk of non-stem cancer
cells, resulting in tumor shrinkage, CSCs may remain
viable and later reestablish the tumor, leading to
relapse.8 Tumors with increased expression of genes
associated with CSCs have also been correlated with
lower overall survival in breast and lung cancers.9
Stemness of CSCs may lead to tumorigenicity
The heterogeneous high tumorigenicity of CSCs may
be a direct result of their stemness. In both normal
stem cells and CSCs, stemness is defined by the
characteristics of self-renewal and differentiation.8
Unlike normal stem cells, which differentiate into
healthy, mature, cell types, CSCs differentiate into
cancer cells. The stemness of CSCs is maintained by
several signaling pathways that are overexpressed
and overactivated, including JAK-STAT, Wnt/β-catenin,
Hedgehog, Nanog, Notch, TGF-β, Hippo-YAP/TAZ,
and PI3K/Akt.10-14 These stemness pathways maintain
stemness and promote tumorigenicity. This makes
CSCs phenotypically different from non-stem cancer
metastasis.13,15 After spreading to a distant site, they can
undergo mesenchymal-epithelial transition and become
tumorigenic, colonizing the new site.15 This is a potential
mechanism for how CSCs contribute to metastasis and
recurrence. Some evidence suggests that EMT and
stemness may be coupled, as they are mediated by
many of the same factors.16
CSCs are highly resistant to conventional
cancer therapies
Although current chemotherapies and radiotherapy
can kill most non-stem cancer cells, CSCs remain
highly resistant.17,18 Further, conventional therapies
have been shown to increase the percentage of CSCs
within malignant residual tumors.19,20 Many mechanisms
that mediate the therapy resistance of CSCs have been
identified, including overactivated stemness signaling.10
A key implication of the CSC model for cancer treatment
is that both CSCs and non-stem cancer cells should be
targeted to reduce tumor recurrence and metastasis.19,21
Several approaches to targeting CSCs are being studied,
including stemness-associated signaling pathways
that may mediate tumorigenesis, metastasis, and
resistance.1,22 The next generation of cancer therapeutics
is in development with investigational agents designed
to inhibit stemness pathways.1
cells and confers therapy resistance.4
Epithelial-mesenchymal transition (EMT)
of CSCs may lead to metastasis
CSCs are also able to transform to a mesenchymal
state by the process of EMT. In this state, CSCs become
highly migratory and invasive and therefore prone to
Learn more at www.bostonbiomedical.com
Boston Biomedical is developing the next generation of cancer therapeutics
with drugs designed to inhibit cancer stemness pathways. Clinical trials are
underway with the goal of reducing recurrence and metastasis.
References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol.
2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and
Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the
ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 8. Reya T, Morrison SJ, Clarke
MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer
stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast
cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S. Mechanism
of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification of
selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679.
20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting stemness
is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.
EDU-NPS-0108 6/2016 ©2016 Boston Biomedical
10
| July 25, 2016 | Healio.com/HemOnc
11
| July 25, 2016 | Healio.com/HemOnc
Originally published in HemOnc Today | June 10, 2016
Originally published in HemOnc Today | June 25, 2016
Pembrolizumab improves long-term
outcomes in advanced melanoma
Upfront autologous HSCT superior to novel
therapies for multiple myeloma
F
orty percent of patients with advanced melanoma achieved 3-year
OS with pembrolizumab, according to long-term follow-up of the KEYNOTE-001 study.
Patients derived benefit from pembrolizumab (Keytruda, Merck) regardless of prior treatment with ipilimumab
(Yervoy, Bristol-Myers Squibb).
“These data confirm that pembrolizumab provides a long-term survival
benefit for patients with advanced melanoma,” Caroline Robert, MD, PhD,
head of the dermatology unit at Institute Gustave-Roussy in Paris, said in a
press briefing. “The response rate contrasts with past results from patients
with this disease. The data show durable responses in one-third of patients,
with complete durable responses that
are visible after stopping treatment.”
Pembrolizumab received accelerated approval for advanced melanoma in September 2014 based on
data from KEYNOTE-001. Data from
KEYNOTE-002 also has shown that
pembrolizumab prolongs PFS compared with chemotherapy, and in
KEYNOTE-006, pembrolizumab extended OS and PFS compared with
ipilimumab for patients with advanced
melanoma.
Prior to the approval of ipilimumab
in 2011, median survival for advanced
melanoma had been less than 1 year,
Robert said.
Robert and colleagues conducted long-term follow-up of patients
treated in the KEYNOTE-001 study
to determine 3-year OS. The analysis included 655 patients — enrolled
into ipilimumab-naive and -treated cohorts — assigned 2-mg/kg or
10-mg/kg doses of pembrolizumab
every 3 weeks or 10 mg/kg every 2
weeks until intolerable toxicity, disease
progression or investigator decision to
stop treatment. Seventy-five percent of
patients had received one or more previous therapies and 52% had received
ipilimumab.
Following pembrolizumab discontinuation, researchers followed up with
patients every 3 months to assess OS.
Median follow-up was 32 months
(range, 24-46); all patients were followed for a minimum of 2 years.
Mean treatment duration was 11.3
months and 21% of patients continued
pembrolizumab beyond the data cutoff
date of Sept. 18, 2015.
Overall, 358 patients died. The
3-year OS rate was 40% and median
OS was 23.8 months (95% CI, 20.2-29).
OS rates appeared similar across
treatment regimens, with the highest
median OS being 25.9 months (95%
CI, 18.9-41.8) in the cohort that received 10 mg/kg every 2 weeks.
The rate of 3-year OS was 41% both
in cohorts who had and had not previously received ipilimumab. However,
3-year OS was higher in treatment-naive patients (45%), for whom median
OS was 32 months (95% CI, 27.1-not
reached).
Ninety-five
patients achieved
a complete response, 61 of whom
stopped treatment as a result. Response
duration ranged from 17+ months to
43+ months.
Two patients experienced disease
progression after stopping treatment,
Pembrolizumab continues on page 13
PERSPECTIVE
This abstract reports on long-term survival outcomes in patients with advanced melanoma treated with pembrolizumab (Keytruda, Merck) in the KEYNOTE-001 trial. Researchers
report a 40% 3-year OS rate with a median survival of nearly 2
years and a “tail-of-the-curve” phenomenon consistent with
long-term survival benefit with this agent.
Richard D. Carvajal
These data mirror the long-term outcomes with nivolumab
(Opdivo, Bristol-Myers Squibb) reported this year by Hodi
and colleagues at the American Association for Cancer Research Annual Meeting. Their results demonstrated a 42%
3-year OS rate and a 34% 5-year OS rate.
Taken together, these studies demonstrate the remarkable clinical benefit achieved
with PD-1–based immunotherapeutics in patients with advanced melanoma. Additional work is needed to enable us to better select those patients who are best
treated with single-agent anti–PD-1 therapy as opposed to those who may require
combined immunological checkpoint blockade with regimens such as ipilimumab
(Yervoy, Bristol-Myers Squibb) and nivolumab.
Reference:
Hodi FS, et al. Abstract CT001. Presented at: AACR Annual Meeting; April 16-20, 2016; New
Orleans.
— Richard D. Carvajal, MD
NewYork-Presbyterian
Columbia University Medical Center
Disclosure: Carvajal reports a consultant role with Merck.
F
irst-line treatment with autologous hematopoietic stem cell
transplantation prolonged PFS
compared with bortezomib-containing chemotherapy in younger patients with newly diagnosed multiple
myeloma, according to results of a
randomized phase 3 study.
Thus, autologous HSCT should
remain the preferred first-line treatment option over novel therapies for
younger patients with newly diagnosed multiple myeloma, according
to the researchers.
“For more than 2 decades, chemotherapy at the doses requiring
the support of autologous stem cells
has been considered the gold standard for younger and fit patients
with newly diagnosed multiple myeloma,” Michele Cavo, MD, head of
the Seràgnoli Institute of Hematology
at University of Bologna, said during a press briefing. “Over the past
10 to 15 years, therapies with novel,
nongenotoxic drugs have dramatically increased the response rate and
significantly [extended] survival in
previously untreated myeloma patients. Remarkable activity of novel
therapies has recently put into question the role of upfront autologous
stem cell transplantation in multiple
myeloma.”
Cavo and colleagues compared the
efficacy of the VMP chemotherapy
regimen — which consists of bortezomib (Velcade; Takeda/Millennium),
melphalan and prednisone — with
autologous HSCT in 1,266 patients
aged 65 years or younger with newly
diagnosed multiple myeloma.
All patients received induction
therapy with bortezomib, cyclophosphamide and dexamethasone. They
then were randomly assigned to four
cycles of VMP (n = 512) or one to two
courses of high-dose melphalan with
single autologous HSCT (n = 754).
Patients treated in centers with a
tandem HSCT policy were randomly
assigned to receive VMP or single or
double autologous HSCT.
Patients then underwent a second
randomization to consolidation therapy with bortezomib, lenalidomide
(Revlimid, Celgene) and dexamethasone or no consolidation therapy,
followed by lenalidomide mainteUpfront continues on page 15
PERSPECTIVE
With the arrival of noncytotoxic agents in the early 2000s,
the role and timing of high-dose melphalan was evaluated
in several randomized phase 3 studies. Palumbo and colleagues with the European Myeloma Network conducted
two randomized phase 3 trials evaluating lenalidomide (Revlimid, Celgene) and low-dose dexamethasone induction followed by conventional chemotherapy — melphalan, prednisone and lenalidomide in one trial, and cyclophosphamide,
prednisone and lenalidomide in the other — or high-dose
melphalan with autologous stem cell transplant (HDM–ASCT,
Saad Z. Usmani
single or tandem). Both trials showed PFS and OS benefits
with HDM–ASCT but were criticized for not having proteasome inhibitors in induction treatment.
Attal and colleagues then presented the Intergroupe Francophone du Myelome
(IFM) 2009 data — which compared early vs. late HDM–ASCT — at the ASH Annual
Meeting and Exposition in 2015. Results showed a PFS benefit in favor of early HDM–
ASCT. All patients on the IFM 2009 trial received lenalidomide, bortezomib (Velcade,
Takeda/Millennium) and dexamethasone induction and lenalidomide maintenance,
thus quelling concerns about suboptimal induction.
Now, Cavo and colleagues have presented another clinical trial in which bortezomib,
cyclophosphamide and dexamethasone induction was followed by either bortezomib, melphalan and prednisone consolidation or HDM–ASCT (single or tandem).
Data from the study follow the same theme: HDM–ASCT conferred superior PFS. The
PFS benefit was seen in patients with standard- and high-risk cytogenetics and was
more pronounced in the tandem HDM–ASCT arm.
If we are compelled to use best available evidence and data to treat our patients,
then upfront/early HDM–ASCT should remain the standard of care for transplanteligible patients with multiple myeloma.
References:
Attal M, et al. Abstract 391. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015;
Orlando, Florida.
Gay F, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00389-7.
Palumbo A, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402888.
— Saad Z. Usmani, MD, FACP
HemOnc Today Editorial Board member
Levine Cancer Institute, Carolinas HealthCare System
Disclosure: Usmani reports no relevant financial disclosures.
12
| July 25, 2016 | Healio.com/HemOnc
13
| July 25, 2016 | Healio.com/HemOnc
Originally published in HemOnc Today | July 10, 2016
Trastuzumab biosimilar safe, effective for
advanced breast cancer
W
omen with HER-2–positive advanced breast cancer
treated with MYL-1401O,
a biosimilar trastuzumab antibody,
achieved outcomes comparable to
those of women treated with the biosimilar’s FDA–approved reference
product, according to results of a
randomized phase
3 study.
The addition
of
trastuzumab
Hope S. Rugo
(Herceptin, Genentech) — a biologic agent approved
by the FDA in 1998 and now indicated
for women with early- or late-stage
breast cancer — to chemotherapy has
resulted in a 5- to 8-month survival
improvement for women with latestage disease. The addition of 1 year of
trastuzumab to chemotherapy has been
shown to reduce the risk for recurrence
by 10% and improve survival by about
9% in women with early-stage disease.
“Biologic agents are usually targeted
therapies and are costly, limiting access
across the globe,” Hope S. Rugo, MD,
professor of medicine at University of
California, San Francisco, said during a press conference. “Many biologic
agents are losing patent protection
soon or have already lost patent protection in other countries. Biosimilars
have the potential to significantly improve access to expensive agents.”
Regulatory agencies have established requirements for biosimilar approval. They include a demonstration
of structural and functional similarity
to the reference product; a demonstration of similar pharmacokinetics and
pharmacodynamics; and confirmation
of similar safety, efficacy and immunogenicity.
Rugo and colleagues evaluated the
safety, efficacy and immunogenicity of
MYL-1401O (Mylan Inc.) compared
with trastuzumab.
The analysis included data from 458
women treated at 95 sites worldwide.
All women had HER-2–positive metastatic breast cancer, and they had not
received prior chemotherapy or trastuzumab for metastatic disease. Fortyfour percent of women had hormone
receptor–positive disease.
Researchers randomly assigned
patients to MYL-1401O (n = 230) or
trastuzumab (n = 228) with docetaxel
or paclitaxel every 3 weeks for at least
eight cycles. Patients with stable disease
beyond the eighth cycle could continue
to receive the antibody therapy alone
until disease progression or unacceptable toxicity.
Overall response rate at week 24
served as the study’s primary endpoint.
The FDA also asked researchers to calculate ORR ratio as an endpoint, and
the European Medicines Agency asked
for the difference in ORR between the
biosimilar and trastuzumab. Secondary
endpoints included PFS, OS and safety.
At week 24, the ORR was 69.6% for
MYL-1401O and 64% for trastuzumab.
Researchers calculated an ORR ratio
of 1.09 (90% CI, 0.97-1.21; and 95%
CI, 0.95-1.23), meeting the predefined
equivalency margin. The difference in
ORR was 5.5 (90% CI, –1.7 to 12.69;
and 95% CI, –3.08 to 14.04), which also
fell within the required equivalency
range.
Based on 41 events in the biosimilar arm and 48 in the reference product arm, median PFS had not yet been
reached.
The overall antidrug antibody rate
was 2.4% with MYL-1401O and 2.8%
with trastuzumab, consistent with pub-
lished data, Rugo said. The dose-normalized maximum concentration and
area under the curve also were similar
between the two agents.
Safety appeared comparable between study groups, and no significant
changes in cardiac function occurred
in either cohort.
Serious adverse events — which
were primarily hematologic and related
to taxane therapy — occurred in 38.1%
of those assigned the biosimilar and
36.2% of those assigned the reference
product.
Common adverse events included
neutropenia (biosimilar, 27.5%; reference product, 25.2%), febrile neutropenia (4.5% vs. 4.1%), leukopenia (1.6%
vs. 4.9%) and pneumonia (1.6% vs.
2%).
Four fatal events occurred in each
study arm.
“This proposed biosimilar has the
potential to meet the need for an affordable treatment option for patients
with HER-2–positive cancers,” Rugo
said. “This is one of the first trials
of biosimilars in oncology to demonstrate these similar results. Ongoing trials with other biosimilars
should further improve access worldwide to these lifesaving therapies.”
– by Alexandra Todak
n
Reference:
Rugo HS, et al. Abstract LBA503. Presented at:
ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: The study was funded in part by
Mylan. Rugo reports a speakers bureau role
with and honoraria from Genomic Health;
travel expenses from Mylan, Nektar, Novartis,
OBI Pharma and Roche/Genentech; and institutional research funding from Celsion, Eisai,
Genentech, MacroGenics, Merck, Nektar, Novartis, OBI Pharma, Pfizer and Plexxikon. Please
see the abstract for a list of all other researchers’
relevant financial disclosures.
PERSPECTIVE
We expect that the area of biosimilars is going to have a bigger
cost impact than maybe some of the oral
drugs when they go generic. Many of
these biologic drugs are now just coming
off patent, so the whole field of biosimilars is new. We do not know exactly how
it is going to play out, but, of course, the
cost is expected to go down significantly.
Trastuzumab (Herceptin, Genentech) is
no longer one of the most expensive biologic drugs, although it used to be when
Debu Tripathy
it first was approved. It can cost anywhere
from $3,000 to $4,000 a month, whereas some of the newer biologic drugs are four times that price. Still, we expect the price will
come down — we hope by at least half.
For some patients, the price will not make a difference because
insurance covers most infused medications. However, there are
patients who have copays, and it will make a difference for them.
In many parts of the world, where these drugs are simply not
available because of the cost, the availability of a biosimilar would
make a huge difference.
The FDA requires a certain degree of testing to prove the efficacy
and safety of a biosimilar. First, the methods for manufacturing
must be very clearly laid out. Second, the product must have the
same chemical composition and physical and functional properties as the parent drug. Third — and most importantly — the biological effects on patients and on the tumor must be similar, the
pharmacokinetics must be well worked out and, ultimately, the
safety and efficacy must be proven to be similar.
In the randomized, double-blind phase 3 trial, the overall response
rate for MYL-1401O (Mylan) given with a taxane in the first line was
about 70%, compared with 64% for trastuzumab. This was statistically similar and met the threshold that is set for eventual approval
of the drug. In addition, mean serum concentrations over time
were similar, as were fatal adverse events (1.6% in each group).
However, the number of patients who had to discontinue early
due to subclinical or clinical cardiomyopathy was not reported.
For aromatase inhibitors, the level of comfort in prescribing a generic is pretty high. Still, there are some differences between the
Pembrolizumab
continued from page 10
one of whom restarted treatment with
pembrolizumab.
The safety profile of pembrolizumab appeared comparable to data from
other studies. The most common adverse events included fatigue (40%),
itchiness (28%) and rash (23%). Eight
generics and branded drugs. I have had some patients have reactions to the packaging, like the capsule and its coloring. However,
this is uncommon. For the most part, when it comes down to a
single, simple chemical, people feel confident.
However, antibodies are different. They are complicated and you
cannot make an antibody identical to another. Antibodies are not
only encoded proteins from a gene, but they also are folded and
glycosylated, and they undergo many other posttranslational
changes that affect their function. Even though you may show
similar responses in a trial, it does not prove that it is identical beyond a shadow of a doubt. There will be no perfect trial to prove
these agents are 100% identical, and there will always be a small
amount of uncertainty.
How do physicians perceive that level of uncertainty, and how
willing are they to convince their patient, who also may be reluctant? Sometimes reluctance comes more from the patient, who
may consider the biosimilar to be a fake or knockoff. We shouldn’t
think of it that way, but rather as a biosimilar even though we cannot prove it is fully equivalent.
Based on the design of the study, if the confidence intervals are
set narrowly enough — as specified by FDA and other regulatory
agencies — I would generally feel confident. I say that not only as
a scientist and as a clinician, but also as a member of society. We
all have to make sure that, together, we can be a healthy society
by equitable distribution of health care. It is not just about one individual person; it is about making sure that societal health is covered. With runaway drug prices and health care costs — especially
when they do not make a difference in relevant patient outcomes
— we have to make sure we are doing what we can to make medical care available and affordable to everyone.
Biosimilars are an important step in that direction, but we do have
to maintain our vigilance over time that we are doing everything
we can to make sure they are truly biosimilar.
— Debu Tripathy, MD
HemOnc Today Editorial Board member
The University of Texas MD Anderson Cancer Center
Disclosure: Tripathy reports service on the steering committee for a registry study for Genentech/Roche, the manufacturer of Herceptin.
percent of patients discontinued treatment due to adverse events.
“Advanced melanoma is still a very
challenging cancer, which is why it is
so remarkable that such a large proportion of patients see a long-term
survival benefit from this therapy,”
Robert said in a press release. “The
results of this study further demonstrate the potential for long-term ben-
efit with pembrolizumab.” – by Nick
Andrews
n
Reference:
Robert C, et al. Abstract 9503. Presented at:
ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: The study was funded by Merck.
Robert reports consultant/advisory roles with
Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis and Roche. Please see
the abstract for a list of all other researchers’
relevant financial disclosures.
14
| July 25, 2016 | Healio.com/HemOnc
| July 25, 2016 | Healio.com/HemOnc
15
Originally published in HemOnc Today | July 10, 2016
Off-label therapies benefit patients with
advanced, mutated cancers
P
atients with nine different tumor
types benefited from targeted
therapies administered outside
of current drug indications, according to the results of a basket study presented at the ASCO Annual Meeting.
The researchers intend to expand
cohorts of patients with HER-2–amplified colorectal cancer, bladder
cancer and biliary cancer, as well as
BRAF–mutated lung cancer, based on
the observed outcomes.
“An increasing number of targeted
agents for advanced cancer are approved now based on the presence
of molecular abnormalities in the
cancers,” John D. Hainsworth, MD,
senior investigator at Sarah Cannon
Research Institute in Nashville, Ten-
nessee, said during a press conference.
“Major successes in this area include
HER-2–targeted treatment for HER2–positive breast cancer and BRAF–
to the difficulty of identifying the patient population.”
The MyPathway study included
data from 129 patients with advanced
“This trial design is feasible, with patients selected
based on molecular abnormalities in their cancers
rather than on their primary tumor type or
primary site.”
— John D. Hainsworth, MD
targeted treatment for melanoma. We
have known, though, that the same
mutations are found in a wide variety
of other cancers, although at a lower
incidence. It is difficult to test how efficient these same treatments are, due
solid tumors and no available curative therapy. Patients’ tumors harbored the following alterations:
lHER-2 amplification (n = 53),
mutation (n = 23), both (n = 5) or
RBMS-NRG1 fusion (n = 1);
PERSPECTIVE
Razelle Kurzrock
The MyPathway study is both a basket
trial and an umbrella trial. Basket trials
look at genomic alterations across different histologies. For instance, in this
study, if you have a BRAF mutation,
it does not matter if you have breast,
lung or colon cancer — it all goes in
the basket. Yet, it also is an umbrella
trial, because it includes four different
baskets. We are, therefore, getting a lot
of mileage out of this one trial.
It is much more efficient to have one trial with four different
baskets rather than having four basket trials.
The most interesting part of this trial is the HER-2 basket.
Patients with a variety of different tumor types — including colorectal cancers and biliary tumors — are having really nice responses, and this is going to be very important. It
is remarkable that we are seeing responses in diseases like
colorectal cancer from giving a drug that would usually be
given to patients with breast cancer or gastric cancer.
In the future, we will see more basket trials, because they
make a lot of sense. However, organizations and institutions
will need to have a system in place to be able to do them.
It would be really difficult to perform a genomically based
basket trial if genomic sequencing is not part of the practice,
because these alterations are rare, and only very small subsets will have the alterations. For colorectal cancer, it may
only be 2% or 3% that have HER-2 alterations. If you are not
regularly checking for it, you are not going to be able to accrue patients. It is really difficult to have to put 100 patients
on a trial in order to find one who is eligible, so you have to
be doing sequencing regularly.
Further, a lot of academic centers that do clinical trials are
very siloed. Colorectal cancer researchers do not work together with the head and neck cancer researchers. They are
all in their own territories. For a trial like this, you have to
have a system that allows you to work across diseases.
These barriers will not be hard to overcome, but I do not
know that all centers are ready to work with a trial like this
one.
— Razelle Kurzrock, MD
Center for Personalized Cancer Therapy
University of California, San Diego
Disclosure: Kurzrock reports research funding from Foundation
Medicine.
l BRAF V600E (n = 18) or other
(n = 15);
lHedgehog (Hh) PTCH1 (n =7)
or SMO (n = 1); or
l EGFR (n = 6).
Patients enrolled in the trial had
received a median of three (range,
0-10) prior lines of therapy.
The researchers evaluated the use
of therapies targeting these alterations, including trastuzumab (Herceptin, Genentech) and pertuzumab
(Perjeta, Genentech) for patients with
HER-2 amplification; vemurafenib
(Zelboraf, Genentech) for patients
with BRAF alterations; vismodegib
(Erivedge, Genentech) for patients
with Hh alterations; and erlotinib
(Tarceva; Genentech, Astellas) for patients with EGFR mutations.
Investigator-assessed response rate
within the tumor-pathway cohort
served as the study’s primary endpoint.
Eleven patients had insufficient
follow-up data and were not included
in the analysis.
Twenty-nine patients achieved
a partial response or complete response, including one complete response achieved by a patient with
HER-2–amplified colorectal cancer.
Researchers also observed responses in three patients with HER-2–amplified bladder cancer and three with
HER-2–amplified biliary cancer (lung
cancer, n = 2; salivary gland cancer,
n = 1); three patients with BRAF–mutated lung cancer; one case each of
BRAF–mutated ovarian cancer, cancer of unknown primary origin, colon
cancer, pancreatic cancer, and head
and neck cancer; and two patients
with Hh alterations (squamous cell
carcinoma, n = 1; cancer of unknown
primary origin, n = 1).
Three patients with BRAF–mutated lung cancer achieved objective
responses, and two achieved stable
disease. The researchers will expand
this cohort based on these data.
Responses continued up to 11
months. Fourteen responding pa-
tients progressed, at a median of 6
months (range, 3-14) after treatment.
The study design allows for the accrual of up to 500 patients, with expansions for groups that demonstrate
benefit. The researchers intend to incorporate new agents that target additional molecular alterations.
“This trial design is feasible, with
patients selected based on molecular
abnormalities in their cancers rather
than on their primary tumor type
or primary site,” Hainsworth said.
“It offers opportunities for patients
with these molecular abnormalities.”
– by Cameron Kelsall
n
Upfront
sion (HR = 0.76; 95% CI, 0.61-0.94).
This benefit persisted across patient subgroups, including among
patients with revised International
Staging System stage III disease (HR
= 0.52; 95% CI, 0.32-0.84) and highrisk cytogenetics (HR = 0.72; 95% CI,
0.54-0.97).
A greater proportion of patients
assigned transplant achieved at least
a very good partial response (84% vs.
74%; OR = 1.9; 95% CI, 1.42-2.54).
Cox regression analysis results showed randomization to
the transplantation arm independently predicted longer PFS
(HR = 0.61; 95% CI, 0.45-0.82).
“These preliminary results do
support the conclusion that upfront
high-dose chemotherapy and autologous transplant continues to be the
best treatment option for fit patients
with newly diagnosed myeloma, even
in the novel-agent era,” Cavo said.
– by Alexandra Todak
n
continued from page 11
nance until progression or toxicity.
PFS from the time of the first randomization served as the study’s primary endpoint.
Cavo presented data from an interim analysis performed in January after
33% of required events had occurred.
Median follow-up from the time
of the first randomization was 23.9
months.
Although median PFS had not yet
been reached, patients assigned highdose melphalan and autologous HSCT
were less likely than those assigned
VMP to experience disease progres-
Reference:
Hainsworth JD, et al. Abstract LBA11511.
Presented at: ASCO Annual Meeting; June
3-7, 2016; Chicago.
Disclosure: Genentech funded this study.
Hainsworth reports institutional research
funding from Astellas, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Eli
Lilly and Novartis. Please see the abstract for
a list of all other researchers’ relevant financial
disclosures.
Reference:
Cavo M, et al. Abstract 8000. Presented
at: ASCO Annual Meeting; June 3-7, 2016;
Chicago.
Disclosure: The study was funded by the
Haemato Oncology Foundation for Adults in
the Netherlands. Cavo reports honoraria and
travel expenses from and consultant/advisory roles with Amgen, Bristol-Myers Squibb,
Celgene, Janssen and Takeda. Please see the
abstract for a list of all other researchers’ relevant financial disclosures.
TARGETING CANCER STEM CELL
PATHWAYS AND STEMNESS
Not all cells within a tumor are equal
Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new
approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are
highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid
and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2
The CSC model may help explain tumor recurrence
The CSC model is a radical departure from the clonal evolution
model. In the clonal evolution model, all cells within a malignant
tumor have similar tumorigenic activity.5 By contrast, in the CSC
model only a subset of tumor cells, CSCs, have tumor-initiating
capability.2 Cancers are organized in a cellular hierarchy,
with the CSCs at their apex having tumor-initiating capability.5
One important clinical implication of the CSC model is that it
may help to explain why early tumor shrinkage is often poorly
predictive of overall survival.6,7 While conventional therapies kill
the bulk of non-stem cancer cells, resulting in tumor shrinkage,
CSCs may remain viable and later reestablish the tumor,
leading to relapse.8 Tumors with increased expression of genes
associated with CSCs have also been correlated with lower
overall survival in breast and lung cancers.9
Stemness of CSCs may lead to tumorigenicity
The heterogeneous high tumorigenicity of CSCs may be a direct
result of their stemness. In both normal stem cells and CSCs,
stemness is defined by the characteristics of self-renewal and
differentiation.8 Unlike normal stem cells, which differentiate
into healthy, mature, cell types, CSCs differentiate into cancer
cells. The stemness of CSCs is maintained by several signaling
pathways that are overexpressed and overactivated, including
JAK-STAT, Wnt/β-catenin, Hedgehog, Nanog, Notch, TGF-β,
Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways
maintain stemness and promote tumorigenicity. This makes
CSCs phenotypically different from non-stem cancer cells and
confers therapy resistance.4
References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A.
2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives.
World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic
cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S,
ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer.
wClin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line
therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate
endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):13411347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic
role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the
therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid
tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation
in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell
Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S.
Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A,
Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification
of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat
Biol. 2014;90(8):615-621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679.
20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844.
21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting
stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267.
EDU-NPS-0108 6/2016 ©2016 Boston Biomedical
Epithelial-mesenchymal transition (EMT)
of CSCs may lead to metastasis
CSCs are also able to transform to a mesenchymal state by the
process of EMT. In this state, CSCs become highly migratory and
invasive and therefore prone to metastasis.13,15 After spreading
to a distant site, they can undergo mesenchymal-epithelial
transition and become tumorigenic, colonizing the new site.15
This is a potential mechanism for how CSCs contribute to
metastasis and recurrence. Some evidence suggests that EMT
and stemness may be coupled, as they are mediated by many of
the same factors.16
CSCs are highly resistant to conventional
cancer therapies
Although current chemotherapies and radiotherapy can kill
most non-stem cancer cells, CSCs remain highly resistant.17,18
Further, conventional therapies have been shown to increase
the percentage of CSCs within malignant residual tumors.19,20
Many mechanisms that mediate the therapy resistance
of CSCs have been identified, including overactivated
stemness signaling.10
A key implication of the CSC model for cancer treatment is
that both CSCs and non-stem cancer cells should be targeted
to reduce tumor recurrence and metastasis.19,21 Several
approaches to targeting CSCs are being studied, including
stemness-associated signaling pathways that may mediate
tumorigenesis, metastasis, and resistance.1,22 The next
generation of cancer therapeutics is in development with
investigational agents designed to inhibit stemness pathways.1
Learn more at www.bostonbiomedical.com
Boston Biomedical is developing the next generation of cancer therapeutics
with drugs designed to inhibit cancer stemness pathways. Clinical trials are
underway with the goal of reducing recurrence and metastasis.