81110.4155/CLI.13.56 © 2013 Future Science LtdISSN 2041-6792

ConferenCe report

Clin. Invest. (2013) 3(9), 811–81511th International Congress on Targeted Anticancer TherapiesValérie Hélin*1, Ohad Hammer2 & Jean-Pierre Armand3

paris, france, 4–6 March 2013The 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 devel-opment 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 Jean-Charles 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 clini-cal 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 giv-ing 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

“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.”

1Cancer Campus, Villejuif, France 2Pontifax Venture, Herzliya, Israel 3Early Clinical Trials Unit, Gustave Roussy, Villejuif, France *Author for correspondence: E-mail: valerie.helin@cancer-campus.com

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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 can-cer 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 confer-ence 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 targetsThe 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 (anti-PD-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

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 impor-tance of the PD-1 pathway in cancer therapy across multiple indications. Pre liminary data correlating PD-L1 expression in pretreatment tumor biopsies with clinical outcomes will be further explored. Five Phase III tri-als 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 check-point 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 target-ing 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 inhibi-tion 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 sci-entists 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 Amplim-mune (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 associ-ated with other immunotherapies (Yervoy®, high dose IL-2). When asked whether PD-1 antibodies are going to cure metastatic melanoma, Michael Atkins (Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA), who gave the keynote lecture on ‘Targeting immune checkpoints’ replied: “Yes, in 25% of patients.”

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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 oncol-ogy 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 (consump-tion 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 programsSusan 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 there-fore, blocking its secretion could obstruct energy produc-tion. 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 anti-cancer 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 cen-tral 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 IDH1- and 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

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 therapyAntibody-drug conjugates (ADCs) are regarded as highly promising oncology drugs as they are very potent agents with a relatively good safety and pharmaco kinetics pro-file [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 (Adce-tris®) 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, conse-quently, 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 vari-ous technologies. The presentation illustrated the inher-ent complexity involved in ADC development due to the need to optimize multiple components in parallel. Iden-tifying 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 non specific accu-mulation 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 differ-entially 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 collabora-tion 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 clini-cal 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

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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 ovar-ian 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. Find-ings included clinical experience with three dosing regi-mens, 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 mini-mizes 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 mesothelin-targeting 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 immuno genicity, toxicity and short half-life. Still, SS1P demonstrated some efficacy signals alone and in com-bination with other drugs. In order to avoid immuno-genicity, 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 eventThe 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 sched-uled giving examples of the new collaborative partner-ships 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

Garaud, previously head of R&D at Roche and currently consultant for biotechs in drug development.

Stephane Depil (Servier) and Scott Koenig (Macro-Genic, MD, USA) presented their ‘win–win’ partner-ship to develop and commercialize new targeted anti-cancer therapies, based on three preclinical programs using MacroGenic platform technology for generating bi specific antibodies [102]. Under the terms of the agree-ment, MacroGenic will receive a €20 million upfront payment, and Servier has the option to obtain exclusive license to develop and commercialize each program, cov-ering 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 bio-tech specialized in diagnosis kit development and com-mercialization [103]. It is the Jak2 story and its character-ization in myeloprolifrative syndrome in connection with clinical relevancy. They demonstrated how that kind of partnership between an academic institution and a bio-tech 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 dis-eases 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 signif-icant 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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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 anti-angiogenic products for cancer and eye disease treat-ments. 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 glio-blastoma 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 strate-gic alliance with a big pharma to work on additional developments in oncology and to optimize the time-to-market 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 Cen-ter, 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 front-line player in early drug development and then attract the best innovative therapies and collaborations with biotechs and pharmas.

ConclusionThe TAT conference is a great opportunity to ‘feel the pulse’ of oncology drug development. Speakers include clinical oncologists, basic scientists and industry

researchers, which provides a fairly broad spectrum with respect to existing and upcoming trends. The TAT bio-tech 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 partner-ship with the European Society for Medical Oncol-ogy. 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 disclosureO 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 organi-zation 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.

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Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24 (2), 207–212 (2012).

2 Chiche J, Ricci JE, Pouysségur J. Tumor hypoxia and metabolism – towards novel anticancer approaches. Ann. Endocrinol. 74(2), 111–114 (2013).

3 Flygare JA, Pillow TH, Aristoff P. Antibody-drug conjugates for the treatment of cancer. Chem. Biol. Drug Des. 81(1), 113–121 (2013).

■ Websites101 Companies news. Servier concludes a

collaboration and license agreement with EOS for its antitumor drug E-3810. www.sofinnova.fr/?p=4635

102 Press releases. MacroGenics and Servier enter 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

blood-based disorders. www.qiagenmarseille.com/en/press-releases/press-release/list/2006/march/article/ipsogen-licenses-jak2-mutation-test-to-improve-the-diagnosis-of-blood-based-disorders

104 Georgia Research Alliance grant to support international drug development collaboration with GHSU Cancer Center http://news.georgiahealth.edu/archives/tag/sisene