Download 11th International Congress on Targeted Anticancer Therapies

Conference Report
Clin. Invest. (2013) 3(9), 811–815
11th International Congress on
Targeted Anticancer Therapies
Valérie Hélin*1, Ohad Hammer2 & Jean-Pierre Armand3
“The Targeted Anticancer Therapies
conference is a great opportunity to
‘feel the pulse’ of oncology drug
development … [providing] a fairly
broad spectrum with respect to
existing and upcoming trends. The
Targeted Anticancer Therapies biotech
event could become a must to attend
for biotechs developing innovative
therapies in oncology, but also for
investors and pharmas.”
Cancer Campus, Villejuif, France
Pontifax Venture, Herzliya, Israel
3
Early Clinical Trials Unit, Gustave Roussy, Villejuif,
France
*Author for correspondence:
E-mail: [email protected]
1
2
ISSN 2041-6792
Paris, France, 4–6 March 2013
The Targeted Anticancer Therapies (TAT) conference provides a forum
for in-depth discussion of emerging targeted agents for the treatment
of cancer. TAT conferences are characterized by focus on emerging
innovative agents with a cancer-specific molecular target, gathering
the world’s leading oncology Phase I investigators. They attract a mix
of professionals with different backgrounds and roles in academia,
industry and governmental agencies, all having a profound interest in the
development of innovative cancer therapies. More than 500 delegates
registered in 2013. Moreover, this year was organized, as part of the TAT
congress, the first ‘TAT biotech event’. New R&D initiatives often known
as ‘open innovation’ are emerging to bring medicines to patients faster
by facilitating public- and private-sector partnerships and collaborations,
to solve common challenges encountered during the drug discovery and
development process. We strongly believe that disruptive innovative
anticancer therapies will come more and more from small biotechs, and
that academic institutions have an active role to play in the field.
An illustrative example is the collaboration between Gustave Roussy (Villejuif,
France) and the biotech Ethical Oncology Science (EOS; Milan, Italy) for the development of E-3810, a dual inhibitor of VEGF and FGF receptors. Based on impressive
preclinical results with E-3810, Gustave Roussy made a deal with EOS to conduct
a first-in-human trial for the anticancer drug (first patient: July 2011). Initial results
from the Phase I trial demonstrated a good safety profile coupled with promising
activity in breast cancer patients with FGFR-dysregulated tumors. This led JeanCharles Soria, head of the early clinical trials unit at Gustave Roussy, to postulate
that E-3810 is a potential breakthrough in the clinical management of several solid
tumors. Subsequently, Gustave Roussy helped to make a connection with potential
pharma partners to support further clinical development of the drug. In October
2012, EOS announced a collaboration with Servier (Suresnes, France) that entailed
an upfront payment of €45 million [101] . This example demonstrates how early clinical trials that utilize biomarkers for patient selection could make an investigational
targeted agent highly valuable.
The Targeted Anticancer Therapies (TAT) biotech event has been created in this
context to become the international event that offers opportunities for biotechs and
international Phase I experts to interact together and initiate collaborations well before
Phase I trials in oncology.
The TAT biotech event includes B-to-B meetings and an interactive session giving examples of the new collaborative partnerships between biotechs and academic
institutions.
The commitment of the international experts to attend the B-to-B meetings
and discuss their innovative products with biotechs was rapid and enthusiastic. For
10.4155/CLI.13.56 © 2013 Future Science Ltd
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Conference Report Hélin, Hammer & Armand
this first edition, approximately 40 meetings had been
scheduled.
Moreover, as an ancillary event of the TAT biotech
event, a tour of the Paris region’s flagship clinical cancer research centers (Assitance Publique des Hopitaux
de Paris, Institut Curie, Gustave Roussy) and of Sanofi
cancer research center was organised.
Jean-Charles Soria (Gustave Roussy) opened the
conference with an overview of the TAT congress’ scope
this year, which was focused on new molecular targets
and innovative targeted anticancer agents, interactions
between early-phase clinical and translational research,
development of molecular diagnostic and predictive
biomarkers, and methodology for drug/diagnostic
development.
The New Drug Development Organization Honorary
Award was made to Jean-Pierre Armand (Gustave
Roussy) in recognition of his exceptional leadership in
the development of better anticancer medicine. In his
lecture, Armand discussed the importance of Phase I
as a critical step for cancer drug development through
numerous concrete examples.
Three major themes are highlighted in this conference report: PD-1 inhibitors, metabolic drug targets
and antibody–drug conjugates (ADCs). This report will
also focus on examples of new collaborative partnerships
between small biotechs and academic institutions and/or
pharmas.
In 2015, the TAT congress and the TAT biotech event
will return to Paris, France.
New immune checkpoints as drug targets
The PD-1/PD-1 ligand (PD-L1) pathway is a one if the
most active fields in oncology drug development. PD-1
is recognized as an important coinhibitory checkpoint
on T cells, which makes PD-1 inhibition a potential
mechanism for enhancing a patient’s immune system.
Tumor expression of PD-L1 correlates with poor survival
in cancer patients, it is often expressed in solid tumors
and clinical proof-of-concept had been achieved for
PD-1/PD-L1 blockade [1] .
Four PD-1/PD-L1 pathway agents were presented:
Bristol-Myers Squibb’s nivolumab (anti-PD-1), Merck’s
MK-3475 (anti-PD-1), Genentech’s MPDL3280A (antiPD-L1) and GlaxoSmithKline (GSK)/Amplimmune’s
AMP-224 (PD-L2-Fc fusion). The first two drugs are in
late-stage development based on positive Phase I data.
The other two drugs are still in Phase I and initial data
are expected this year.
David Feltquate, (Bristol-Myers Squibb, NY, USA)
described his company’s progress towards developing
nivolumab, a fully human PD-1 antibody. Presented data
entailed remarkable activity in melanoma, lung and renal
cancer, which was characterized by very long duration
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of response (many responders remain progression free
after 2 years). Interestingly, nivolumab appears to have
unusual kinetics of response (some patients respond after
initial progression, some maintain long-term responses
after very short exposure to the drug). Nivolumab can
be administered safely in an outpatient setting to heavily
pretreated patients. These findings support the importance of the PD-1 pathway in cancer therapy across
multiple indications. Pre­liminary data correlating PD-L1
expression in pretreatment tumor biopsies with clinical
outcomes will be further explored. Five Phase III trials of nivolumab in patients with non-small-cell lung,
melanoma and renal cell carcinoma have begun.
Alexander Eggermont (Gustave Roussy) presented
Phase I data in melanoma for MK-3475, a humanized
anti-PD-1 from Merck (NJ, USA). The response rate was
very high (51%) and appeared numerically higher than
that observed with nivolumab. Many of the patients had
been pretreated with Yervoy®, another immune checkpoint antibody targeting CTLA-4. The response rate
in this subpopulation was still quite high (41%), which
proves that failure on one form of immunotherapy does
not preclude benefit with another. Durability of responses
also appeared to be very high, similar to that seen with
nivolumab.
Daniel Chen (Genentech, CA, USA) presented the
rationale and initial results obtained with Genentech’s
MPDL3280A, an antibody targeting PD-L1. In theory,
targeting PD-L1 has two main advantages over targeting PD-1. The first advantage is the ability to inhibit
another receptor on T cells (B7.1), which is also activated
by PD-L1. The second advantage is avoiding the inhibition of PD-L2 binding to PD-1, which could result in
lower toxicity. Clinical activity and one example of robust
tumor shrinkage were demonstrated. In order to improve
the antibody’s safety profile even further, Genentech’s scientists engineered the Fc region to completely eliminate
effector functions. James Smothers (GSK, Brentford,
UK) described AMP-224, an Fc-fused PD-L2 that can
bind PD-1 on T cells, which was licensed from Amplimmune (MD, USA). He presented preclinical results that
may indicate a differentiated mode of action that may
result in a different clinical profile.
There was a consensus among presenters and discuss­
ants that results with both nivolumab and MK-3475 are
some of the most impressive data sets ever seen with a
single drug in solid tumors. The safety profile was also
remarkably good; substantially better than that associated with other immunotherapies (Yervoy®, high dose
IL-2). When asked whether PD-1 antibodies are going to
cure metastatic melanoma, Michael Atkins (GeorgetownLombardi Comprehensive Cancer Center, Washington,
DC, USA), who gave the keynote lecture on ‘Targeting
immune checkpoints’ replied: “Yes, in 25% of patients.”
future science group
11th International Congress on Targeted Anticancer Therapies This could revolutionize the melanoma field, as today
patients with metastatic melanoma have a median overall
survival of 11–13 months with recently approved drugs
(Zelboraf® and Yervoy). For the first time, patients have a
25% chance of long-term remissions with a safe drug that
can be simply injected into them in an outpatient setting.
Metabolic drug targets: the next big thing in
oncology?
TAT provides a glimpse of the industry’s preclinical
pipeline, which often dictates upcoming trends in oncology drug development. Cancer metabolism is definitely
emerging as one of the ‘hot topics’ in oncology and one
can expect to see many programs in the clinic in the
coming 2 years.
The working hypothesis in cancer metabolism is that
cancer cells have a different metabolic profile (consumption and utilization of nutrients) than healthy cells. This
is supported by a growing list of metabolic enzymes that
are mutated or aberrantly expressed in cancer cells.
In theory, inhibition of these enzymes could lead to
anticancer activity while sparing normal cells [2] .
Three companies presented internal cancer
metabolism programs
Susan Critchlow (AstraZeneca, London, UK) presented
the company’s work with inhibitors of MCT, a family of
lactate transporters. Cancer cells produce large amounts
of lactate that has to be secreted out of the cells and therefore, blocking its secretion could obstruct energy production. AZD3965, an MCT1 inhibitor, started in Phase I
trials earlier this year and the company is working on
additional inhibitors for related targets (MCT4).
Richard Wooster (GSK) presented work focusing on
fat production and the enzyme FAS as a target. GSK
developed a potent FAS inhibitor that has a broad anticancer profile. Wooster also presented extensive work on
the metabolic consequences of FAS inhibition, which
further validated the molecule’s profile. FAS inhibition
might be associated with broad side effects, given its central role in fat metabolism; however, the drug appears to
be well tolerated in animal models (no notable liver or
cardiac toxicity). The drug (GSK526) is expected to enter
the clinic this year.
Sam Agresta (Agios, MA, USA) presented Agios’
strategy of identifying genetically defined subsets of
tumors that are addicted to specific metabolic enzymes.
The company’s most advanced programs are the IDH1and IDH2-inhibitor programs, partnered with Celgene
(NJ, USA). IDH1 and IDH2 are part of the Krebs Cycle
and mutations in both enzymes are seen in many tumor
types. Although there is still controversy around the role
of these enzymes and respective mutations in cancer, a
growing body of scientific evidence implicates IDH1
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Conference Report
and IDH2 as important targets for molecularly defined
subsets of patients. Agios plans to investigate its IDH
inhibitors only in patients whose tumors are found to
have IDH dysregulation.
Immunoconjugates for cancer therapy
Antibody-drug conjugates (ADCs) are regarded as highly
promising oncology drugs as they are very potent agents
with a relatively good safety and pharmaco­k inetics profile [3] . There are two companies with validated ADC
technologies that generated US FDA-approved drugs:
Seattle Genetics (WA, USA) and Immunogen (MA,
USA). Seattle Genetics’ brentuximab vedotin (Adcetris®) is approved for Hodgkin’s lymphoma and Roche’s
trastuzumab emtansine (Kadcyla™ [T-DM1]) is
approved for HER2-positive breast cancer. Both agents
have robust activity as single agents and a relatively
benign safety profile.
Based on initial results with Adcetris and Kadcyla,
there has been a surge of interest in ADC and, consequently, in a number of programs that are currently in
development. Unfortunately, most of the other ADCs
that entered the clinic could not replicate the clinical
profile observed with Kadcyla and Adcteris. Still, some
ADCs, including the ones presented in the meeting,
demonstrated clinical activity. Many others still have
not generated clinical data.
Veronique Blanc (Sanofi, Paris, France) started the
ADC session with a comprehensive overview of the various technologies. The presentation illustrated the inherent complexity involved in ADC development due to the
need to optimize multiple components in parallel. Identifying the ‘sweet spot’ for all parameters (target epitope,
payload type, linker type, amount of payload per ADC
and so forth ) is very challenging. Another important
property of ADCs is that they have toxicities that are
unrelated to the target but stem from non­specific accumulation in healthy tissues. This explains why in most
cases, ADCs cannot be dose escalated beyond 2–4 mg/kg
and also implies that even when the target is very differentially expressed on tumors, general toxicity will appear.
Sanofi has been an early mover in the ADC field via a
collaboration with Immunogen. To date, the collaboration yielded three ADCs that entered Phase I trials. One
ADC (AVE9633, anti-CD33) was discontinued due to
lack of efficacy, whereas the two ADCs targeting CD19
and CA6 are still in development.
Stuart Lutzker (Genentech) provided an overview of
Genentech’s ADC pipeline. Genentech is by far the most
active developer of ADCs, with eight programs in clinical trials and many more in preclinical development. All
eight programs utilize Seattle Genetics’ technology.
The presentation started with a recap of Kadcyla’s data
in breast cancer. Lutzker emphasized that Kadcyla proved
Clin. Invest. (2013) 3(9)
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Conference Report Hélin, Hammer & Armand
superior to active approved chemotherapy regimens in
two randomized trials (Phase III in second-line patients,
Phase II in first-line patients). This superiority is driven
in part by the ‘deeper’ (more durable) responses ADCs
can induce.
Lutzker’s presentation showed initial clinical data
with a MUC16 ADC, currently in Phase I for ovarian and pancreatic cancer. The ADC appears to have
activity in ovarian cancer with multiple cases of tumor
shrinkage. Responses were specifically observed in
patients with high MUC16 expression, which bodes well
for the ability to identify the right patient population
for this ADC.
Anas Younes (MD Anderson Cancer Center, TX,
USA) presented clinical results for SAR3419, Sanofi’s
CD19 ADC based on Immunogen’s technology. Findings included clinical experience with three dosing regimens, which led to objective responses across various
types of B-cell malignancies. SAR3419 had a response
rate of approximately 30% at the higher doses and was
well tolerated with ocular toxicity as the dose-limiting
toxicity. Sanofi is using a modified regimen that minimizes this side effect and is expected to present Phase II
results this year.
Raffit Hassan (National Cancer Institute, Bethesda,
MD, USA) gave a very interesting talk on mesothelintargeting immunoconjugates. Hassan focused on the
National Cancer Institute-developed immunotoxin,
SS1P, which is comprised of an antibody and a potent
toxin. Conceptually, immunotoxins are similar to
ADCs but they suffer from several limitations, such as
immuno­genicity, toxicity and short half-life. Still, SS1P
demonstrated some efficacy signals alone and in combination with other drugs. In order to avoid immunogenicity, an improved version entered Phase I, with data
expected this year.
Hassan also mentioned Bayer’s BAY 94–9343, an
ADC powered by Immunogen’s technology. Based on
activity with SS1P, which validated mesothelin as a
target, BAY 94–9343 has the potential to demonstrate
early signs of efficacy. Importantly, as an ADC, it can
be administered repeatedly, whereas immunotoxins can
be given for only one to two cycles.
TAT biotech event
The TAT biotech event 2013 includes B-to-B meetings
devoted to biotechs developing innovative therapies and
looking for international Phase I experts as potential
partners or advisors. An interactive session was scheduled giving examples of the new collaborative partnerships between biotechs, academic institutions and/or
pharmas. This year was the first edition; approximately
40 meetings had been scheduled. The biotech session
was co-chaired by Jean-Pierre Armand and Jean-Jacques
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Garaud, previously head of R&D at Roche and currently
consultant for biotechs in drug development.
Stephane Depil (Servier) and Scott Koenig (MacroGenic, MD, USA) presented their ‘win–win’ partnership to develop and commercialize new targeted anticancer therapies, based on three preclinical programs
using MacroGenic platform technology for generating
bi­specific antibodies [102] . Under the terms of the agreement, MacroGenic will receive a €20 million upfront
payment, and Servier has the option to obtain exclusive
license to develop and commercialize each program, covering the world with the exception of the USA, Japan,
Korea and India. If Servier exercises such options, Macro­
Genic will receive clinical and registration milestones as
well as royalties.
Isabelle Pelletier-Bressac (Gustave Roussy Transfert,
Villejuif, France) and Vincent Fert’s (Qiagen, Venlo,
Netherlands) presentation demonstrated the successful
case of a licensing from an academic institution to a biotech specialized in diagnosis kit development and commercialization [103] . It is the Jak2 story and its characterization in myeloprolifrative syndrome in connection with
clinical relevancy. They demonstrated how that kind of
partnership between an academic institution and a biotech could become a long-term story, based on a truthful
relationship, with new licences signed along the years.
Laurent Levy (LYRIC, Lyon, France) presented the
OncoTherapy Science (Kawasaki, Japan) experience
with Centre Léon Bérard (Lyon, France). OncoTherapy
Science is a biotech developing innovative anticancer
therapies on the basis of the outcomes from research by
Yusuke Nakamura, the head of the Japanese national
cancer institute. The story began in 2008, at the BioJapan
conference with a meeting between Yusuke Nakamura
and Jean-Yves Blay, an oncologist from Centre Léon
Bérard and an expert in synovial sarcoma, a rare diseases that affects approximately 100 people per year in
France. Blay was impressed by the preclinical results of
OncoTherapy Science technology relying on the use of
a specific monoclonal antibody coupled to radiation. In
May 2010 OncoTherapy Science set up a subsidiary in
Lyon (OTS France) to prepare the ‘first-in-man’ study
of their drug. The first clinical trials began in January
2012 in three French reference centers for sarcoma care:
Léon Bérard in Lyon, Gustave Roussy and the Institute
Bergonié in Bordeaux, France.
The technology developed by OTS also showed significant effects in other types of cancers such as colorectal
and stomach. Simon Baconnier, head of OTS said that If
the R&D of these more upstream projects is concentrated
in Japan for the moment, nothing precludes that they are
not further developed in part in Lyon.
Jean Marsac, (Sisene Oncology Inc., Paris, France)
and Olivier Rixe (Georgia Health Sciences University,
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11th International Congress on Targeted Anticancer Therapies GHSU Cancer Center, GA, USA) ended the biotech
session with another illustrative example of a ‘win–
win’ partnership between a biotech and an academic
institution for innovative drug development [104] .
Sisene’s objective is to develop innovative antiangiogenic products for cancer and eye disease treatments. The presentation was focused on Sisene’s plan
for the development of their NOV/NOV C product.
Marsac explained how his company try to solve the
financing gap issue that therapeutic biotechs often have
to face between the preclinical results and the first
proof-of-concept in human.
To overcome this critical step, Sisene chose glioblastoma as a target for a fast-track registration, and
made a deal with a Phase I unit to achieve the clinical
proof-of-concept and then Sisene will look for strategic alliance with a big pharma to work on additional
developments in oncology and to optimize the time-tomarket and the first commercial revenues. The Phase I
unit is in the USA so they created a US subsidiary
(Sisene Onco, Inc.).
Rixe, head of the Phase I unit at GHSU Cancer Center, explained how he convinced his hierarchy to allocate
a specific clinical budget for proof-of-concept in Phase I
of innovative drugs. A success in Phase I automatically
makes the product more appealing for financial partners
like pharmas or investors. The interest of the institution,
aside from a financial return, is to become a major frontline player in early drug development and then attract
the best innovative therapies and collaborations with
biotechs and pharmas.
Conference Report
researchers, which provides a fairly broad spectrum with
respect to existing and upcoming trends. The TAT biotech event could become a must to attend for biotechs
developing innovative therapies in oncology, but also
for investors and pharmas.
Stakeholders
■■The TAT series was established in 2002 and is offered
by the NDDO Education Foundation, in a partnership with the European Society for Medical Oncology. The TAT congress series is managed, on behalf
of the NDDO Education Foundation by Congress
By Design (Amsterdam, The Netherlands).
■■The TAT 2013 President was Jean-Charles Soria.
■■The TAT 2013 scientific committee chairman was
Giuseppe Giaccone (Georgetown Lombardi Comp­
rehensive Cancer Center).
■■The TAT biotech event was chaired by Jean-Pierre
Armand and Cristiana Sessa (Oncology Institute of
Southern Switzerland; Bellinzona, Switzerland).
■■The TAT biotech event and the Paris region visit tour
was co-organized by Cancer Campus and the Paris
Region Economic Development Agency.
Financial & competing interests disclosure
O Hammer is an employee of Pontifax, which has equity in many
companies including some that are related to this review. Personally,
O Hammer owns shares in Seattle Genetics. The authors have no
other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart
from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
Conclusion
The TAT conference is a great opportunity to ‘feel
the pulse’ of oncology drug development. Speakers
include clinical oncologists, basic scientists and industry
Reference
1
2
3
■■ Websites
Topalian SL, Drake CG, Pardoll DM.
Targeting the PD-1/B7-H1(PD-L1) pathway
to activate anti-tumor immunity. Curr. Opin.
Immunol. 24 (2), 207–212 (2012).
101 Companies news. Servier concludes a
Chiche J, Ricci JE, Pouysségur J. Tumor
hypoxia and metabolism – towards novel
anticancer approaches. Ann. Endocrinol.
74(2), 111–114 (2013).
102 Press releases. MacroGenics and Servier enter
Flygare JA, Pillow TH, Aristoff P. Antibodydrug conjugates for the treatment of cancer.
Chem. Biol. Drug Des. 81(1), 113–121 (2013).
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collaboration and license agreement with
EOS for its antitumor drug E-3810.
www.sofinnova.fr/?p=4635
development and commercialization agreement
for novel anti-cancer drug.
www.macrogenics.com/press_releases-310.html
103 Press release. IPSOGEN licenses JAK2
mutation test to improve the diagnosis of
Clin. Invest. (2013) 3(9)
blood-based disorders.
www.qiagenmarseille.com/en/press-releases/
press-release/list/2006/march/article/
ipsogen-licenses-jak2-mutation-test-toimprove-the-diagnosis-of-blood-baseddisorders
104 Georgia Research Alliance grant to support
international drug development
collaboration with GHSU Cancer Center
http://news.georgiahealth.edu/archives/tag/
sisene
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