PAGE 59 / SEPTEMBER 10, 2005
`
`GIST Shows Response to SU11248—
`If Looking for Right Biomarkers
`
`By Paula Moyer
`
`O RLANDO, FL—Antiangio-
`
`genic agents like SU11248
`show considerable promise in
`patients with solid tumors that
`have been resistant to other therapies—
`if the clinician knows which biomarkers
`to look for. In several presentations
`here at the ASCO Annual Meeting,
`investigators identified those markers
`and showed the agent’s potential in
`gastrointestinal stromal tumors (GIST)
`and neuroendocrine tumors.
`“The key issue here for the practic-
`ing oncologist is the excitement of prob-
`ing the activity of new and highly
`potent antiangiogenic agents with new
`biomarkers,” said George D. Demetri,
`MD, who served as the senior investi-
`gator for two studies involving the role
`of SU11248 in GIST.
`“We have chosen to explore rather
`novel biomarkers of activity in our
`GIST trials.”
`Dr. Demetri, Director of the Center
`for Sarcoma and Bone Oncology at
`Dana-Farber Cancer Institute and
`
`Associate Professor of Medicine at
`Harvard Medical School, said regard-
`ing these and other studies of SU11248
`in GIST that the findings may hold
`promise for other treatment-resistant
`solid tumors.
`In one study investigators wanted
`to know whether SU11248 would
`affect the endothelial and tumor com-
`partments in GIST lesions.
`The team focused on this particu-
`lar potential treatment response
`because GIST lesions contain activat-
`ing mutations of both KIT and platelet-
`derived growth factor receptor
`(PDGFR), which are both tyrosine
`kinase receptors.
`Because SU11248 had been shown
`to inhibit these mutations in patients
`who had developed resistance to ima-
`tinib, the investigators wanted to
`know if this pattern could also indicate
`a response to SU11248.
`Therefore, they obtained paired
`tumor biopsies from 19 GIST patients
`who were being treated with SU11248.
`Biopsies were performed at baseline
`and after at least 14 days of treatment
`
`with SU11248 during the first treatment
`cycle, and were then examined with
`both immunofluoroescence and laser-
`scanning cytometry to quantify the
`apoptosis of endothelial and tumor
`cells and assess the microvessel density
`and phosphorylation of PDGFR-␤ and
`other tyrosine-kinase receptors.
`In eight of the 19 pairs of tumor
`samples, there was documented clinical
`benefit, defined as having either a par-
`tial response according to Response
`Evaluation Criteria in Solid Tumors
`(RECIST) or stable disease for more
`than six months. The remaining 11
`patients had progressive disease.
`Compared with baseline,
`tumors from patients with clinical
`benefit had a significant decrease
`of 15%
`in phosphorylated
`PDGFR-␤ activity in the tumor
`cell compartment.
`Among the responders, two
`patients had a partial response
`and an average decrease of 23% in
`phosphorylated PDGFR-␤ activi-
`ty. The six with stable disease had
`(continued on page 60)
`
`George D. Demetri, MD: “The key
`issue here for the practicing
`oncologist is the excitement of
`probing the activity of new and
`highly potent antiangiogenic
`agents with new biomarkers. We
`have chosen to explore rather
`novel biomarkers of activity in our
`GIST trials.”
`
`Ovarian Cancer
`continued from page 58
`
`lated that it might be best used in com-
`bination with conventional chemother-
`apy. After being immobilized by
`RAD001, ovarian cancer cells would be
`more vulnerable to the cytotoxic drugs,
`Dr. Testa explained.
`
`Robert J. Morgan, MD: “The
`rapamycin analogues are early
`promising agents targeting a
`promising pathway.”
`
`This strategy, it was hoped, would
`increase five-year survival substantial-
`ly, Dr. Mabuchi said.
`Dr. Testa pointed out that since
`RAD001 targets a specific pathway,
`there should be fewer side effects than
`with conventional chemotherapy. “In
`the mice, it appears to do nothing to
`other tissue,” he said.
`
`The strategy is to block
`mTOR downstream of
`AKT, therefore avoiding
`the side effects of a
`direct attack.
`
`Important Signal Transduction
`Pathway in Variety of Cancers
`
`Robert J. Morgan, MD, a staff physician
`in
`the Department of Medical
`Oncology and Therapeutics Research
`at City of Hope National Medical
`Center, said that AKT has been shown
`to be an important signal transduction
`pathway in a variety of cancers.
`Among them: Leukemia, lymphoma,
`and numerous solid tumors.
`“This is allowing researchers to
`design targeted therapies that interfere
`with this pathway and there-
`fore with tumor development,”
`he said.
`At least two dozen phar-
`maceutical companies are try-
`ing to target the AKT pathway,
`according to Dr. Testa. Some
`have already reached Phase I/II trials.
`The rapamycin analogues “are
`early promising agents targeting a
`promising pathway,” said Dr. Morgan,
`who was not involved with the
`research.
`RAD001 is made by Novartis
`Pharmaceuticals, which did not fund
`this research.
`
`Refining Strategies
`That Target EGFR
`Yet another targeted therapy being test-
`ed in ovarian cancer is gefitinib, an
`inhibitor of epidermal growth factor
`receptor (EGFR). In other new research
`presented at the meeting, other Fox
`Chase researchers reported that gefi-
`tinib appears to be effective only in
`women with mutations in the tyrosine
`kinase portion of EGFR.
`For the study, led by Russell
`Schilder, MD, of the Clinical Molecular
`Genetics Laboratory, archived tissue
`was examined from Phase II trials
`designed to assess the efficacy and tol-
`erability of gefitinib in patients with
`recurrent or persistent ovarian
`carcinoma or primary peritoneal
`cancer.
`“We did a blinded mutation-
`al analysis, and the one patient
`who had the only objective
`response to gefitinib during the
`23-month trial had a mutation in
`the tyrosine kinase portion of
`EGFR,” he said. In contrast, no
`mutations were observed in 23 of
`the cases with no measurable
`response to the drug.
`Overall,
`the researchers
`detected mutations in the tyro-
`sine-kinase domain region in two
`of 56 (3.6%) of ovarian carcinomas.
`“This is proof of principle, a win-
`dow into the future suggesting that
`by screening for such mutations, we
`can improve the response rate,” Dr.
`Schindler said. “The practical issue
`right now is that if only 4% of
`women have the mutation, screening
`
`Russell Schilder, MD: “This is proof
`of principle, a window into the
`future suggesting that by
`screening for such mutations, we
`can improve the response rate.
`The practical issue now is that if
`only 4% of women have the
`mutation, screening for this
`particular mutation is not practical.
`Ultimately we will screen a patient
`for a variety of different mutations
`and different targets before
`choosing the appropriate
`therapy.”
`
`for this particular mutation is not
`practical.
`“Ultimately we will screen a
`patient for a variety of different muta-
`tions and different targets before
`choosing the appropriate therapy,” he
`predicted.
`O
`T
`
`Ex. 1067-0001
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`

`

`PAGE 60 / SEPTEMBER 10, 2005
`
`SU11248
`continued from page 59
`
`an average decrease of 11% of this
`marker. In contrast, tumors in nonre-
`sponding patients had an increase in
`PDGFR-␤ activity of 11%.
`
`“Monocytes could be a very
`useful way to discern
`responders from non-
`responders. They’re not rare
`cells, and it shouldn’t be
`difficult to find them.”
`
`The tumors in patients with clinical
`benefit showed a 3.6-fold increase in
`endothelial cell apoptosis and a sixfold
`increase in tumor cell apoptosis.
`Among patients with progressive dis-
`ease, there was little or no change in
`endothelial and tumor cell apoptosis
`compared with baseline.
`
`Circulating Endothelial
`Cells & Monocytes
`
`In another study of SU11248 in GIST,
`investigators found that both endothe-
`lial cells and monocytes may be valu-
`able biomarkers to tell if a patient has
`responded to treatment.
`“We have to look for different bio-
`markers other than tumor shrinkage
`when we use antiangiogenic agents,”
`said principal investigator Anat
`Norden-Zfoni, MD, a fellow in the
`Vascular Biology Program at Children’s
`Hospital Boston.
`“Antiangiogenesis causes less
`tumor shrinkage than we typically look
`for in chemotherapy. So we need to
`show benefit from treatment in a differ-
`ent way. We looked at both circulating
`endothelial cells and monocytes and
`found that responders had higher lev-
`els of both after treatment compared
`with non-responders.”
`A rise in circulating endothelial
`cells, which express vascular endothe-
`lial growth factor (VEGF), is a sign that
`the tumor’s vasculature is being
`destroyed, she explained.
`The manufacturer of SU11248,
`Pfizer, which makes the drug under the
`trade name Sutent, supplied the drug
`and placebo tablets, but provided no
`other funding, Dr. Norden-Zfoni said.
`She and her colleagues theorized
`that monocytes would decrease but that
`circulating endothelial cells would
`increase in responders, because mono-
`cytes express VEGF receptor-1 (VEGF-
`R1) and circulating endothelial cells
`express VEGF-R2.
`By targeting tumor vasculature,
`treatment with GIST could cause more
`circulating endothelial cells to be
`released as the result of blood vessel
`destruction in tumors, she said.
`
`A total of 73 patients with metastat-
`ic, imatinib-resistant GIST were
`enrolled in the Phase 1/2 trial. Patients
`received 50 mg of SU11248 orally once
`daily for either 14 or 28 days in each
`six-week treatment cycle, followed by a
`14-day hiatus.
`Complete blood counts were
`obtained before and after treatment and
`circulating endothelial cells were
`assessed with four-color flow cytome-
`try in a subset of 16 patients.
`In the overall patient base, mono-
`cyte levels decreased by 54%, from 770
`cells/␮l at baseline to 350 cells/␮l on
`Day 14. Not surprisingly, monocytes
`then increased during the hiatus in 64
`patients. Surprisingly, though, the
`decrease in monocytes was greater in
`patients with progressive disease, aver-
`aging 58%, then in patients with clinical
`benefit, who had an average decrease of
`48%.
`Among the subset of 16 patients in
`whom the circulating endothelial cells
`were assessed, the levels were similar
`at baseline. In the seven patients with
`clinical benefit, there was a rise in
`mature circulating endothelial cells
`after six to 20 days of therapy, rising
`from a baseline average of 1.6 cells/␮l
`to an average of 24.4 cells/␮l).
`Among the nine patients with pro-
`gressive disease, four had a rise in cir-
`culating endothelial cells, from a base-
`line average of 3.9 cells/␮l to a post-
`treatment average of 6.8 cells/␮l. There
`was also a statistically significant dif-
`ference in the rate of change per day in
`circulating endothelial cells, so that
`those with clinical benefit had an aver-
`age daily increase of 3.8 cells/␮l com-
`pared with an average daily decrease
`of 0.01 cells/␮l in those with progres-
`sive disease.
`
`“The findings support
`the hypothesis that
`SU11248-mediated
`inhibition of angiogenesis
`contributes to clinical
`responses in
`GIST patients.”
`
`Dr. Norden-Zfoni added that
`monocytes may be a more feasible bio-
`marker, because there are more of them
`than there are circulating endothelial
`cells, which are rare and require color
`cytometry to detect.
`
`Neuroendocrine Tumors
`
`In other research, investigators are
`exploring the potential for SU11248 in
`metastatic, unresectable neuroendo-
`crine tumors (NETs). Matthew Kulke,
`MD, the principal investigator, noted
`that conventional chemotherapy has
`limited efficacy in such patients.
`“This is a tumor type in which
`
`standard cytotoxic chemotherapy has
`had mixed results, and it has been asso-
`ciated with significant toxicities,” he
`said in a follow-up telephone interview.
`“The most exciting aspect of our
`results is that treatment with SU11248
`represents a completely different way
`of thinking about treating NETs, with a
`VEGF inhibitor. This may be the begin-
`ning of a new paradigm for thinking
`about how to treat these tumors.”
`
`Matthew Kulke, MD: “The most
`exciting aspect of our results is
`that treatment with SU11248
`represents a completely different
`way of thinking about treating
`neuroendocrine tumors, with a
`VEGF inhibitor. This may be the
`beginning of a new paradigm for
`thinking about how to treat these
`tumors.”
`
`Dr. Kulke, a medical oncologist at
`Dana-Farber Cancer Institute and
`Assistant Professor of Medicine at
`Harvard Medical School, explained that
`because neuroendocrine tumors are
`known to be highly vascular and to
`express high levels of both VEGF and
`VEGFR, the hope was that SU11248
`would be a feasible treatment method.
`In an ongoing Phase II study, 106
`patients with advanced, unresectable
`NETs were treated with repeated six-
`week cycles of SU11248 at a dose of 50
`mg daily for four weeks, followed by a
`two-week hiatus. Conventional chemo-
`therapy was allowed, as was treatment
`with octreotide in patients who had
`begun treatment with it before the
`study.
`Among the 93 evaluable patients,
`the responses were as follows: Among
`the 52 patients with islet cell NETs,
`seven (13.5%) were partial responders,
`and 40 (77%) had stable disease, with
`three patients (5.5%) having progres-
`sive disease. The status of the remain-
`ing two was not yet confirmed.
`Among the 39 patients with carci-
`noid NETs, two (5.1%) were partial
`responders, and 36 (92.3%) had stable
`disease, with one patient (2.6%) experi-
`encing progressive disease.
`Among the evaluable patients, 86
`had treatment-related toxicities. Grade
`3/4 toxicities included diarrhea in three
`(3%), fatigue in 23 (26%), glossodynia in
`
`three (3%), nausea in six (7%), neu-
`tropenia in 12 (13%), thrombocytopenia
`in eight ( 9%), and vomiting in five
`(6%). Other toxicities were infrequent,
`Dr. Kulke reported.
`
`Findings May Help
`Tailor Treatment
`
`In separate comments, experts dis-
`cussed the impact of the investigators’
`findings.
`“Since SU11248 inhibits multiple
`kinases, it is important to understand
`why different tumors respond, so that
`in the future we can best identify
`patients who will respond to this drug
`and ‘personalize’ treatment plans for
`individual patients,” said Michael
`Heinrich, MD, Professor of Medicine in
`the Division of Hematology/Medical
`Oncology at Oregon Health & Science
`University Cancer Institute.
`“In [the first study] the investiga-
`tors found that tumor biopsies
`obtained from patients whose tumors
`responded had evidence of inhibition
`of PDGFR-␤ while nonresponding
`tumors actually had evidence of
`increased angiogenesis. These
`findings—along with those of
`the other study—support the
`hypothesis that SU11248-mediat-
`ed inhibition of angiogenesis
`contributes to clinical responses
`in GIST patients.
`“There are some additional
`clinical implications of this
`study,” Dr. Heinrich added. “In
`some cases, like GIST, conven-
`tional imaging may not reliably
`detect tumor response or may do
`so only after a significant time
`delay of weeks to months.
`“These results suggest that in the
`future, we might be able to use tests
`like circulating endothelial cells to help
`determine clinical response to antian-
`giogenic agents.”
`Continued study is the next step,
`said Margaret von Mehren, MD,
`Director of the Sarcoma Oncology
`Program at Fox Chase Cancer Center.
`In the study of circulating endothe-
`lial cells and monocytes, “the investi-
`gators note that patients who respond
`or have greater than six months stable
`disease on the agent have less of a
`decline in monocyte counts and a
`greater rise in circulating endothelial
`cells,” she said.
`“The significance of the change in
`monocytosis is unclear, and may reflect
`a healthier patient subject, or may be a
`marker of response as suggested by the
`authors.”
`The rise in circulating endothelial
`cells, however, has been seen as a sign
`of activity in other antiangiogenic
`agents, Dr. von Mehren added.
`“In the other GIST study, the
`decrease in PDGFR-␤ phosphorylation
`would suggest that the agent is having
`an antiangiogenic role. In addition
`there were greater numbers of apoptot-
`ic circulating endothelial and tumor
`cells in patients deriving clinical bene-
`fit. This underscores the role of the
`agent as an antiangiogenic drug.”
`O
`T
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`Ex. 1067-0002
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`