`
`Elmer Wachtel (American, 1864-1929), Capistrano Mission
`Oil on canvas. 15" x 25.50". Courtesy of the Fleischer Museum.
`Scottsdale, Anzona
`
`What New Drugs, Biologics, and Treatment Approaches Show Promise
`in Breast Cancer?
`
`
`The multiplicity ofnew interventions for breast cancer
`will challenge our capabilityto clinically evaluate them.
`
`DR HORTOBAGYI
`
`A numberofnew agents are being developed concurrently, including cytotoxins, hormonal agents, and biologic approaches (Table). There are a number ofnew
`anthracyclines, particularly liposomal anthracyclines. There are ongoing clinical trials with liposomal daunorubicin and liposomal doxorubicin. At M.D. Anderson, we
`developed liposomal anamyein, which is a new anthracycline that 1s not a p- glycoprotein substrate; in the laboratory,it is effective in doxorubicin-resistant tumors.It is
`unclear whether liposomal daunorubicin or liposomal doxorubicin is more effective than doxorubicin. However, the pharmacokinetics andtoxicity profiles of the agents
`certainly differ. Thus, these liposomal agents might create some opportunities for different combinations and scheduling.
`
`A numberof antifolates are undergoingclinicaltrials, although I think that only edatrexate will survive for breast cancer. Other antifolates are currently undergoing
`investigation for Pneumocystis carinii infections and otherindications.
`
`The anthrapyrazoles, of which losoxantrone is the best known, continue to be investigatedin clinical trials. This agent demonstrates response rates ranging from 50% to
`60%, which are similar to and possibly exceed those of the standard anthracyclines. An ongoingclinicaltrial is comparing losoxantrone/ cyclophosphamide with
`doxorubicin/cyclophosphamide. Other anthrapyrazoles, including teloxantrone, piroxantrone, and CI-958, are also being studied in clinical trials. These other agents
`demonstrate no obvious advantage compared to losoxantronein preclinical studies.
`
`A large numberof thymidylate synthase inhibitors are in clinical development. Raltitrexed and capecita-bine are completing phaseII clinical trials and nearing initiation of
`phase III trials. Uracil/tegafur, $1, and a variety of others coming primarily from Japan are also under evaluation.
`
`A numberof agents inhibit the degradation of fluoropyrimidines. For example, Glaxo Wellcome has a compound (776C85)that has just entered phase II trials. There
`are new vinea alkaloids of which vinorelbineis the latest to be approved by the US Food and Drug Administration. However,there are at least two other new vinca
`alkaloids beginning phase I tnals, primarily in Europe.
`
`I am aware of one new taxanein clinical trials now and probably several that are approaching phase I trials. We have a hexadecylphosphocholine, miltefosine, that has
`been approved and is commercially available in Germany and other European countries. It is a moderately effective topical agent for local recurrences of breast and
`other tumors. Several camptothecin analogues appearto have someactivity in breast cancer with reported response rates ranging from 15% to 25%. These include
`irinotecan (CPT- 11), topotecan, and 9-aminocamptothecin 9-AC).
`NewTreatments for Breast Cancer
`
`Spindie Porsans
`Paciitaxe!
`Docetaxel
`Virvoreliers
`Liposomal Delivery
`Coxorubicin
`Daunorubicin
`Anarnyein
`Antifoiates
`Edatrexaie
`Trirnetrexate
`Thymidylate synthase inhibitors
`Raltiirexed
`Capecitabine
`Uracilfegatun
`$1
`ZW53511
`LyY2a1614
`
`Topoisomerase Inhibitors
`Topo |/Camptothecin analogues
`Topolacan
`irinotecan (CPT-11)
`$-aminocamptotnecin (9-AG)
`Tope tl
`Anthrapyrazoles
`Losoxantnane
`Teloxantrone
`
`Vaccines
`
`Angiogenesis Inhibitors
`oof, integrin anlagonists
`Matrix matalloproléinase inhibitors
`Urokinase plasminogen activators
`Platelet factor 4
`Endostatin
`Thrombaspondin
`Vitaxin,
`Marimastat
`Antimetabolites
`Gemcitabine
`Aromatase inhibiiors
`4-OHA
`Fadrozale
`Vornnale
`Letroxale
`Anastrozole
`
`Other Hormonal Treatments
`GAH agonets
`Gaserelin
`Leuprotide
`Amipropestins
`Mitepristane
`Onapristone
`Antiestrogens
`
`AstraZeneca Exhibit 2037 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
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`Piroxantrone
`Chose
`
`Toremitene
`Oroloxitens
`iCi-182789
`Palliative Therapy
`
`jexadecyiphesphochotins
`
`
`Miltelosine Sirontium-53
`
`Bislogic Therapy
`Anti-Her-2/neu
`growth factor recaptor
`al growth factor
`
`Atleast two important monoclonalantibodiesare directed at growth factors or growth factor receptors in clinical trials, including anti- HER-2/neu (4D5) and
`antiepidermal growth factor receptor (EGFR; C225). There are several other monoclonal antibodies against other components ofepithelial cells that also are in clinical
`trials.
`
`Atleastsix different vaccines are bemg developed against breast cancer. A large number of agents have been developed to reverse MDR-mediated drug resistance,
`and a numberof genetic modification approachesare in clinical trial. We have an anti- HER-2/neutranscription repression methodthat already has accruedfive patients
`in a phaseIclinical trial. We have a p53 transfer program using a retroviral method. We have also recently completed a phase I study transfecting the MDR-gene into
`hematopoietic stem cells to allow posttransplant cytotoxic therapy.
`
`Thus, there are many ongoing research trials and with the potential number of combinations and permutations, the possibilities are infinite.
`
`DR SLEDGE
`
`Wehave been very interested in another area, angiogenesis inhibitors. When I look in our chemotherapy tool box, it seems we are always waiting for that one
`chemotherapeutic agent to cure breast cancer. | believe we may wait a long time if we seek oneparticular drug to be the answer. I am impressed with the idea that we
`may beable to subvert the tumor's microenvironmentrather than just simply kill the tumor. Fascinating data have come from Judah Folkman's groupin recent years.23
`Basically, in the setting of micrometastatic disease, the tumoris already actively dividing but is held in check because it lacks an appropriate vasculature to allow
`growth. The tumor becomescapable of aggressive growth whenit is able to induce real blood vessel growth into the tumor microenvironment. This angiogenic activity
`may occur at any point in the life of the tumor.
`
`There are a numberof approaches to subvert the tumor microenvironment and shut down the angiogenic process. These include drugs that will block the ligands for
`blood vessel- growth factor receptors, including alpha,beta, integrin antagonists. Since alpha,beta, integrinis essentially foundonly on proliferating vascularepithelial
`cells. In the laboratory, one can. induce apoptosis in these cells using an antagonist to alpha,beta, integrin. This drug will soon be entering clinical tals.
`
`The matrix metalloprotemase inhibitors are important potential inhibitors of the angiogenesis process. The urokinase plasminogenactivator family also is anothertarget
`that may be useful in terms of the angiogenic process. Platelet factor 4 is anothertarget that is being evaluated in the angiogenic process. Overall, there are eight or 10
`ditferent parts of the angiogenic process that represent potential therapeutic targets.
`
`I believe that lack of knowledge on howto use these novel biologic approaches will be the primary investigational problem. We may have greatdifficulty testing these
`approachesin our current paradigm of testing drugs in metastatic disease. One cannotreally expect that these drugs are going to affect a 2-kg tumor witha fully
`developed vasculature. However, one could easily rationalize evaluation ofthese agents in a micrometastatic disease setting, which might be similar to giving insulin toa
`diabetic. In other words, these agents may not cure the disease but potentially will allow the disease to be kept in checkindefinitely. Thus, knowing howtotest these
`agents will be a major challenge in the next few years.
`
`Another important treatment approach comes from a different direction than new drugs. Specifically, I think learning howto select the drugs appropriate for each
`individual patient is an important area of research and has been a recurring theme in our discussions. An interesting exampleofthis is the anti- HER-2/neu product. We
`have known for many years that HER-2/neu is a reasonable prognostic factor in breast cancer. In a micrometastatic disease setting, patients who are HER-2/neu-
`positive are more likely to relapse and die than those who are HER-2/neu-negative. As such, HER-2/neuhas joined the exhaustive list of prognostic factors in breast
`cancer.
`
`However, the interesting thing about HER-2/neuis that it may be apredictive as well as prognostic factor. It may define who respondsto a particular therapy. In the
`metastatic hormonaltherapy setting, for instance, a HER-2/neu-positive patient is highly unlikely to respond to hormonal therapy, regardless of hormone receptor
`status. In the adjuvant setting, in the spmoff trial from the CALGBtrial that evaluated dose intensity, the only patients who benefited from high-dose doxorubicin-based
`chemotherapy were patients who were HER-2/neu-positive.*
`
`Thus, in the future, we may be able to use an oncogene such as HER-2/neu orother factors to predict who will benefit from our standard regimens. Theoretically, this
`should allowour standard regimens to be used in patients mostlikely to benefit and allow usto avoid treating the patients who will experienceonly toxicity. In the
`future, we may be able to segment our breast cancer population into several different subgroups for whom particular therapies will be most effective. We have always
`done this with hormonereceptors, but increasingly I think we are going to do this with these new predictive factors.
`
`DR ROWINSKY
`
`Asfar as the classic cytotoxic agents are concermed, the next very active agents that we are testing in San Antonioare the thymidylate synthase inhibitors. As Dr
`Hortobagyi mentioned, at least one or twoof these agents, particularlyraltitrexed, has demonstrated activity in breast cancer. Other thymidylate synthase inhibitors,
`including ZN933 11 and LY231514, also are currently undergoing evaluation in breast cancer. These drugs are very different in structure and pharmacologicactivity.I
`think we are going to see a numberoftrials that attempt to determine the roles of these agents in a numberofother tumors.
`
`Weare close to evaluating clinically a numberofagents directed against proliferative signaling. Two or three compoundswill soon begin clinicaltrials. These
`compounds may prove very exciting and valuable. Anotheractive agentofinterest 1s gemcitabine. Wearelikely to see increasing evaluation ofthis drug both alone and
`in combination in a numberof tumor types, including breast cancer. For example, we have just completed a phase I trial of gemcitabine plus paclitaxel in which we were
`able to administer both drugs using full single-agent doses.
`
`Like Drs Hortobagyi and Sledge,I believe that other exciting drugs on the horizon include epidermal growth factor receptor antagonists, endothelial growth factor
`receptor antagonists, antiangiogenesis agents, and matrix metalloprotemase inhibitors. These drugs have tremendouspotential because they are nontoxic and can be
`
`AstraZeneca Exhibit 2037 p. 2
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`administered orally for long periods. The problem is going to be discerning the mosteffective use for these agents because weare unlikelyto see significant activity in
`phaseI andII clinical trials. Long-term adjuvantstudies with large patient numbersare required with long follow-up periods in order to truly understandtheroles of
`these agents in cancer treatment.
`
`References
`
`1. Hanania EG, Giles RE, KavanaghJ, et al. Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not
`contribute to post-transplant hematopoietic recovery following intensive systemic therapy. Proc Natl Acad Sci US A. 1996;93:15346-15351.
`2. Folkman J. Clinical applications of research on angiogenesis. NV Engl JMed. 1995;333:1757- 1763.
`3. OReilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.
`Cell. 1994;79:3 15-328.
`4. Muss HB, Thor AD, Berry DA,et al. c-ErbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl JMed.
`1994;330: 1260-1266.
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