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  林家齊醫師11th法國巴黎標靶治療會議.會議心得

Targeted Anticancer Therapies
Paris, France 4 - 6 Mar 2013
Chia-Chi (Josh) Lin, MD, PhD
Director of Phase I Center
Department of Oncology
National Taiwan University Hospital

Earlier this month, I attended the TAT (Targeted anticancer therapies) congress in Paris. This conference focuses exclusively on targeted therapies for cancer, one of the most active areas in drug development. As a small conference (~500 participants), it does not generate a lot of high profile clinical data, still, it is a great opportunity to “feel the pulse” of oncology drug development. Speakers include clinical oncologists, basic scientists and industry researchers, which provide a fairly broad spectrum with respect to existing and upcoming trends.
Here, I focus on three major themes from the meeting: PD-1 inhibitors, antibody drug conjugates (ADCs) and cancer metabolism.

The PD-1 race
The first plenary session focused on drugs that inhibit PD-1 signaling. This class of drugs is probably the most exciting thing in oncology, based on unprecedented results across several tumor types. At the session, it was interesting to see the various approaches pursued by different companies in terms of choice of therapeutic agent and clinical strategy.
The session was preceded by a keynote lecture by Michael Atkins (Georgetown University), who gave an overview of the evolving landscape of immune checkpoints. Atkins, who has been a strong advocate of immunotherapy before it became so popular, emphasized that there are probably baseline parameters that dictate whether a patient responds to immune checkpoint inhibitors or not. A lot of it has to do with the microenvironment of the tumor including infiltration of immune cells and the various mechanisms cancer cells use to evade the immune system. This “immunogenic profile” can explain the dramatic variability in response to immunotherapy (some patients can be cured while others are inherently resistant).
4 PD1 programs were presented: BMS’s nivolumab (anti-PD1), Merck’s MK-3475 (anti-PD1), Genentech’s MPDL3280A (anti PD-L1) and GSK / Amplimmune’s AMP-224 (PD-L2-Fc fusion). The first 2 are in late stage development based on positive phase I data. The other two are still in phase I and initial data are expected this year.
David Feltquate (BMS) reviewed published results with nivolumab (BMS-936558), a fully human PD1 antibody. Nivolumab demonstrated remarkable activity in melanoma, lung and renal cancer. Dr. Feltquate emphasized the depth of responses (many responders are progression free after 2 years) and the unusual kinetics of response (some patients respond after initial alleged progression, some maintain long term responses after very short exposure to the drug).
Alexander Eggermont (Institut Gustave Roussy) presented phase I data for MK-3475, a humanized anti-PD1 in melanoma. Response rate was very high (51%) and appeared numerically better than that observed with nivolumab. As this trial started in 2011, many of the patients had been treated with Yervoy, another immune checkpoint antibody. 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 immunotherapy. Durability of responses also appeared very high, similarly to that seen with nivolumab.
It was very interesting to see how representatives from Genentech and GSK tried to differentiate their programs from the standard PD-1 antibodies.
Daniel Chen (Genentech) presented the rationale and initial results with MPDL3280A, an antibody targeting PD-1 ligand (PD-L1). PD-L1 is expressed by tumor cells and can suppress the immune system by binding PD-1 on T cells in the tumor microenvironment. 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. Chen stated they are seeing clinical activity and presented one example of robust tumor shrinkage. In order to improve safety profile even further, Genentech’s scientists engineered the Fc region to completely eliminate effector functions (ADCC, CDC)
It is important to note that BMS also has a PD-L1 antibody but decided to move ahead with nivolumab, since it was more active. Therefore, it is unclear whether blocking B7.1 is a worthwhile approach. The opportunity to have a better safety profile looks somewhat irrelevant to me given the excellent safety profile with PD-1 antibodies. Nevertheless, it is hard to make any definitive conclusions until results are published.
James Smothers (GSK) discussed AMP-224, which was licensed from Amplimmune in 2010. This is an Fc-fused PD-L2 which can bind PD-1 on T cells. Although often viewed as interchangeable with PD-1 antibodies, GSK claims it has a differentiated mode of action that may result in a different clinical profile. Similarly to MPDL3280A’s case, there is still no evidence for a differentiated clinical profile (let alone superior one) versus PD-1 antibodies.
Everybody agrees that results with both nivolumab and MK-3475 are one 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 replied: “Yes, in 25% of patients”. To put this in context, patients with metastatic melanoma have a life expectancy of 11-13 months with recently approved drugs (Zelboraf, Yervoy). To date, curing these patients has been either impossible or required complicated, expensive and toxic treatments (e.g. IL-2, TILs). For the first time, patients have a 25% chance of long term remissions with a safe drug that can be simply injected to them at every clinic.
My take home message from this session is that BMS is still well positioned with nivolumab, which has the most comprehensive data set and development program (5 phase III trials). Merck’s MK-3475 looks very active and numerically better (in melanoma) and is not too far behind with a very large (500 patients) randomized phase II trial. The trial is evaluating 2 dosing regimens of MK-3475 vs. chemotherapy and might enable accelerated approval.
Genentech’s and GSK’s approaches, although scientifically interesting, are both 1-2 years behind with products that might be safer but could also be inferior in terms of clinical benefit. Given the indications are fatal cancers and the benign safety profile seen with nivolumab and MK-3475, it will be hard to beat nivolumab or MK-3475 based on a better safety profile.
Aveo’s investors should follow PD-1 inhibitors as well, as this class of drugs could displace VEGFR inhibitors as the preferred treatment in renal cancer. Nevertheless, approval of PD-1 inhibitors in 1st line RCC is still years away (BMS’ phase III trial is in 2nd line patients). Moreover, combining the two classes of drugs could be a very powerful approach and Aveo’s tivozanib is the best tolerated and therefore the most combinable VEGFR inhibitor. BMS is evaluating nivolumab with sunitinib or pazopanib in renal cancer in phase I trials.

Antibody drug conjugates
ADCs are another hot topic in oncology as they are very potent agents but have a relatively good safety and PK profile. There are two companies with validated ADC technologies that generated FDA approved drugs: Seattle Genetics and Immunogen. Seattle Genetics’ Adcetris is approved for Hodgkin’s lymphoma and Roche/Genentech’s Kadcyla (T-DM1) is approved for 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 in interest in ADC and consequently in number of programs 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 other still haven’t generated clinical data.
Veronique Blanc (Sanofi) 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 etc.) is very challenging. Another important point was that ADCs have toxicities that are unrelated to the target but stem from non-specific 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 collaboration with Immunogen. To date, the collaboration yielded 3 ADCs that entered phase I. One ADC (AVE9633, anti-CD33) was discontinued due to lack of efficacy, whereas 2 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 and capable developer of ADCs, with 8 programs in clinical trials and many more in preclinical development. All 8 programs utilize Seattle Genetics’ technology, making Genentech’s ADC pipeline Seattle Genetics’ most valuable growth engine for 2013.
The presentation started with a recap of Kadcyla’s data in breast cancer. Lutzker emphasized Kadcyla proved superior to active approved chemotherapy regimens in 2 randomized trials (phase III 2nd line, phase II in 1st line). This superiority is driven in part by “deeper” (more durable) responses ADCs can induce. He then discussed Genentech’s earlier stage ADC pipeline and focused on the company’s CD22, CD79b and MUC16 programs.
Data for the CD22 and CD79b in NHL had previously been presented at ASH. Both ADCs appear very active with a 40%+ response rate in patients treated at clinically relevant doses. Genentech has a creative clinical strategy for the two ADCs: It is comparing them in a randomized phase II trial in combination with Rituxan. Interestingly, the trial is designed to allow crossover between the arms, which could provide important insights on resistance mechanisms (e.g. are they target or toxin related?).
To me, the most exciting part in Lutzker’s presentation was initial clinical data with a MUC16 ADC, currently in phase I for ovarian and pancreatic cancer. I originally thought this program was discontinued but it turns out that not only it is still active, 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.
Overall, Genentech’s ADC pipeline appears to be progressing very well, with more data expected this year. As discussed, this is extremely positive for Seattle Genetics, which is eligible for milestone payments and royalties for each program.
Anas Younes (MD Anderson Cancer Center) presented clinical results for SAR3419, Sanofi’s CD19 ADC based on Immunogen’s technology. Younes presented clinical experience using 3 dosing regimens, which included objective responses across various types of B cell malignancies. SAR3419 had a ~30% response rate at the higher doses and was well tolerated with ocular toxicity as the dose limiting toxicity. Sanofi is using a modified regimen which minimizes this side effect and is expected to present phase II results this year.
Overall, my personal impression is that SAR3419 is slightly inferior to other ADCs for NHL (primarily Genentech’s CD22 and CD79b programs and Seattle Genetics’ Adcetris for CD30+ DLBCL). However, cross trial comparisons are unreliable. In addition, as it employs a different payload (albeit with a similar mechanism) from the above ADCs, it might have a different activity spectrum. Despite being the first to put a next-generation ADC for NHL in the clinic, Sanofi has been somewhat slow in developing SAR3419. Consequently, it lost its early mover advantage and is now facing a lot of competition.
Raffit Hassan (National Cancer Institute) gave a very interesting talk on mesothelin-targeting immunoconjugates. He focused on the NCI-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 a 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. Phase I results will be presented at the next AACR meeting (April 2013). 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 given repeatedly whereas immunotoxins can be given for only 1-2 cycles.

Cancer metabolism – the next big thing in oncology?
Meetings like TAT provide 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 anti-cancer activity while sparing normal cells.
At TAT, 3 companies presented internal cancer metabolism programs.
Susan Critchlow (AstraZeneca) presented the company’s work with inhibitors of MCT, a family of lactate transporters. Cancer cells produce large amounts of lactate, which has to be secreted out of the cells, therefore, blocking its secretion could obstruct energy production. AZD3965, an MCT1 inhibitor, started phase I 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 (fatty acid synthase) 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 looks like a very bold choice, 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) presented Agios’ strategy of identifying genetically defined subsets of tumors which are addicted to specific metabolic enzymes.  The company’s most advanced programs are the IDH1 IDH2 inhibitors programs, partnered with Celgene. 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, Agios tells an elegant story supported by a large body of scientific evidence. The company plans to investigate its IDH inhibitors in biomarker-defined patient populations.

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