`
`Elmer Wachtel (American, 1864-1929), Capistrano Mission.
`Oil on canvas, 15" x 23.50". Courtesy of the Fleischer Museum.
`Scottsdale, Arona
`
`What New Drugs, Biologics, and Treatment Approaches Show Promise
`in Breast Cancer?
`
`
`The multiplicity ofnew interventions for breast cancer
`will challenge our capability to clinically evaluate them.
`
`DR HORTOBAGYI
`
`A number ofnew agents are being developed concurrently, including cytotoxins, hormonal agents, and biologic approaches (Table). There are a number of new
`anthracyclines, particularly liposomal anthracyclines. There are ongoingclinical trials with liposomal daunorubicin and liposomal doxorubicin. At M.D. Anderson, we
`developed liposomal anamyecin, which is a new anthracycline that is 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 and toxicity profiles of the agents
`certainly differ. Thus,these liposomal agents might create some opportunities for different combinations and scheduling.
`
`A numberof antifolates are undergoing clinical trials, although I think that only edatrexate will survive for breast cancer. Other antifolates are currently undergoing
`investigation for Pneumocystis carinii infections and other indications.
`
`The anthrapyrazoles, of which losoxantrone is the best known, continue to be investigated in clinicaltrials. This agent demonstrates response rates ranging from 50% to
`60%, which are similar to and possibly exceed those of the standard anthracyclines. An ongoing clinicaltrial is comparing losoxantrone/ cyclophosphamide with
`doxorubicin/eyclophosphamide. 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 clinicaltrials and nearinginitiation of
`phase III trials. Uracil/tegafur, $1, and a variety of others coming primarily from Japan are also underevaluation.
`
`A numberofagents inhibit the degradation offluoropyrimidines. For example, Glaxo Wellcome has a compound (776C85)that has just entered phaseII 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 phaseI trials, primarily in Europe.
`
`I am aware of one new taxanein clinical trials now and probably several that are approaching phaseI 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 ofbreast and
`other tumors. Several camptothecin analogues appear to have some activity in breast cancer with reported responserates ranging from 15% to 25%. These include
`irinotecan (CPT- 11), topotecan, and 9-aminocamptothecin @-AC).
`NewTreatments for Breast Cancer
`
`Spindle Poisons
`Paclitaxel
`Docetawel
`Virorelbene
`Liposomal Delivery
`Doxorubicin
`Daunorubicin
`Anarnyom
`Antifotates
`Edatroxate
`Trirnetrexate
`Thymidylate synthase inhibitors
`Raltitrexed
`Capecitabine
`Uraciltegatur
`$1
`2N93311
`Ly2ai614
`
`Topoisomerase inhibitors
`Topo l/Camptothecin analogues
`Topolecan
`irinotecan (CPT-11)
`$-aminocamptotmecin (9-AG)
`Tope ti
`Anthrapyraroles
`Losoxantrane
`Teloxantrone
`
`Vaccines
`
`Angiogenesis inhibitors
`orf, integrin anlaganists
`Matrix metalionrotéinase inhibitors
`Urokinase plasminogen activators
`Platelet factor 4
`Endostatin
`Thrombaspendin,
`Vitaxin
`Marimastal
`Antimelabolites
`Gemcitabine
`Aromatase inhibiiors
`4-OHA
`Fadrozale
`Vornaoie
`Letrozale
`Anastrorola
`
`Other Hormonal Treatments
`GNAH agoriests
`Goseretin
`Louprolide
`Antiprogestins
`Mifepristare
`Onapristone
`Amtiestrogens
`
`AstraZeneca Exhibit 2037 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
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`Toremifene
`Oroloxitens
`iCi-182789
`Palliative Therapy
`Hisphasphonates,
`Pamidronate
`Chodron
`
`Sirontivm-82
`
`Atleast two important monoclonal antibodies are 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 componentsof epithelial cells that also are in clinical
`tals.
`
`Atleast six different vaccines are being developed against breast cancer. A large number of agents have been developed to reverse MDR-mediated drug resistance,
`and a number of genetic modification approachesare in clinical trial. We have an anti- HER-2/neutranscription repression method that already has accruedfive patients
`in a phaseI clinical trial. We have a p53 transfer program using a retroviral method. We have also recently completed a phase I study transfecting the MDR-geneinto
`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 chemotherapytool box, it seems we are always waiting for that one
`chemotherapeutic agent to cure breast cancer. I believe we may wait a long time if we seek oneparticular drug to be the answer. I am impressed with the idea that we
`maybe able to subvert the tumor's microenvironmentrather than just simply kill the tumor. Fascinating data have come from Judah Folkman's groupin recent years.
`Basically, in the setting of micrometastatic disease, the tumor is already actively dividing butis held in check becauseit lacks an appropriate vasculature to allow
`growth. The tumor becomescapable of aggressive growth when it 1s able to induce real blood vessel growth into the tumor microenvironment. This angiogenicactivity
`may occur at any point in the life ofthe tumor.
`
`There are a numberof approaches to subvert the tumor microenvironment and shut down the angiogenic process. These include drugsthat will block the ligands for
`blood vessel-growth factor receptors, including alpha,beta, integrin antagonists. Since alpha,beta,integrin is essentially found only on proliferating vascular epithelial
`cells. In the laboratory, one can induce apoptosis in these cells using an antagonist to alpha,beta, integrin. This drug will soon be entering clinicaltrials.
`
`The matrix metalloproteinase inhibitors are important potential inhibitors of the angiogenesis process. The urokinase plasminogen activator family also is another target
`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
`differentparts of the angiogenic process that represent potential therapeutic targets.
`
`I believe that lack of knowledge on howto use these novel biologic approacheswill be the primary investigational problem. We may havegreat difficulty testing these
`approachesin our current paradigm oftesting drugs in metastatic disease. One cannotreally expect that these drugs are goingto affect a 2-kg tumor withafully
`developed vasculature. However, one could easily rationalize evaluation ofthese agents in a micrometastatic disease setting, which might be similarto giving insulin to a
`diabetic. In other words,these agents may not cure the disease but potentially will allow the disease to be kept in check indefinitely. Thus, knowing howtotest these
`agents will be a majorchallenge in the next few years.
`
`Another important treatment approach comes from a different direction than new drugs. Specifically, I think learning how to select the drugs appropriate for each
`individual patient is an important area of research and has been a recurring themein our discussions. An interesting example ofthis is the anti-HER-2/neu product. We
`have known for many years that HER-2/neuis 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 whe are HER-2/neu-negative. As such, HER-2/neuhas joined the exhaustivelist 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 patientis highly unlikely to respond to hormonal therapy, regardless of hormone receptor
`status. In the adjuvantsetting, in the spinoff 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/neuorother factors to predict who will benefit from our standard regimens. Theoretically,this
`should allowour standard regimensto be used in patients mostlikely to benefit and allow us to avoid treating the patients who will experience only toxicity. In the
`future, we may be able to segmentour 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 goingto do this with these new predictive factors.
`
`DR ROWINSKY
`
`Asfar as the classic cytotoxic agents are concerned, the next very active agents that we are testing in San Antonioare the thymidylate synthase inhibitors. As Dr
`Hortobagyi mentioned, at least one or two of these agents, particularlyraltitrexed, has demonstrated activity in breast cancer. Other thymidylate synthase inhibitors,
`including ZN93311 and LY231514,also are currently undergoing evaluation in breast cancer. These drugs are very different in structure and pharmacologicactivity. I
`think we are gomg to see a numberoftrials that attempt to determine the roles of these agents in a numberof other tumors.
`
`Weare close to evaluating clinically a numberof agents directed against proliferative signaling. Two or three compounds will soon begin clinical trials. These
`compounds may prove very exciting and valuable. Another active agentofinterest is gemcitabine. Weare likely 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 phaseI trial of gemeitabine 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 most effective use for these agents because weare unlikelyto see significant activity in
`phase I andII clinicaltrials. Long-term adjuvant studies with large patient numbers are required with long follow-up periods in orderto truly understand the roles 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 U S 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. NV Engl JMed.
`1994;330: 1260-1266.
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`AstraZeneca Exhibit 2037 p. 3
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