At the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (October 22-26, San Francisco, CA), eight Exelixis compounds were the subjects of 13 poster presentations, in which investigators reported data from clinical trials or preclinical studies of XL647, XL880, XL184, XL820, XL844, XL518, XL147, and XL765.
On this page, you can read summaries of the data presented, view posters and abstracts, and listen to the company’s analyst/investor meeting which was held in conjunction with the conference.
XL647 +
XL647, an inhibitor of EGFR, HER2, and VEGFR2 kinases, was the subject of two poster presentations:
Summary of Abstract #B124: In this phase 2 study in previously untreated, clinically selected non-small cell lung cancer patients, XL647 continued to show encouraging anti-tumor activity when administered on an intermittent schedule (once daily for 5 days every 2 weeks). Consistent with data reported in September 2007 at the IASLC meeting, 68% of the 34 patients evaluable for tumor response had clinical benefit: 10 patients had partial responses (eight confirmed, two not yet confirmed) and 13 patients had stable disease as their best response. All seven patients with documented activating EGFR mutations experienced tumor shrinkage (six with partial responses and one with stable disease), and three patients with wild type EGFR had partial responses. XL647 was generally well tolerated in this patient population.
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Summary of Abstract #B242: In this phase 1 dose-escalation study evaluating daily dosing of XL647, 11 of 21 patients assessable for tumor response receiving doses of XL647 ranging from 75 to 300 mg achieved stable disease for at least three months. The exposure to XL647 with daily dosing at the maximum tolerated dose (MTD) of 300 mg in the study was approximately twofold higher over a 28-day cycle compared to the exposure observed previously at the MTD of 350 mg for the intermittent dosing regimen. XL647 was generally well tolerated, and related Grade 3 adverse events were infrequent. No Grade 3 or greater skin rash was reported in this study. A total of ten serious adverse events were reported in six patients; of these events, two were considered possibly or probably related to XL647.
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XL880, an inhibitor of MET and VEGFR2 kinases, was the subject of two poster presentations:
Summary of Abstract #B249: In an ongoing phase 2 trial of XL880 in patients with papillary renal cell carcinoma (PRC), 15 of 19 patients (79%) with measurable disease evaluable for tumor response have had a decrease in tumor size (4-33%), including one patient with a partial response. All 19 evaluable patients with at least one post-baseline tumor assessment have had stable disease for at least three months, including 12 patients with stable disease for 6 - 15+ months. In 16 patients evaluable for safety endpoints, the majority (72%) of adverse events (AEs) related to XL880 were Grade 1, 21% were Grade 2, and 5% were Grade 3 or higher. The Grade 3 AEs were hypertension in three patients. There were no Grade 4 or 5 AEs that were judged related to XL880 treatment. A total of 15 serious adverse events (SAEs) in seven patients were reported, of which three were considered related to XL880 (two events of vomiting in one patient and hypertension in another patient).
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Summary of Abstract #B248: Investigators also presented results of a phase 1 study of XL880 in patients with advanced solid tumors. Consistent with data previously reported from this study, XL880 was generally well tolerated when given once daily over a 28-day cycle. Ten of 22 patients showed stable disease for at least three months. In a preliminary analysis of plasma samples from 21 patients, statistically significant changes in pharmacodynamic biomarkers were detected in this clinical trial consistent with effects reported with other anti-angiogenic agents. This finding is also consistent with the hypertension that has been observed in patients receiving XL880.
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XL184, a potent inhibitor of MET, RET,and VEGFR2 kinases, was the subject of one poster presentation:
Summary of Abstract #A152: In an ongoing phase 1 trial of XL184 in patients with advanced malignancies, anti-tumor activity has been observed in a variety of cancers at doses that are not associated with significant toxicity. There were 33 patients available for safety, pharmacokinetic and tumor response analyses as of the June 22, 2007 cutoff; further data were also provided for six additional patients after the cutoff. Of seven patients with medullary thyroid cancer (MTC), three have had partial responses (2 confirmed and 1 unconfirmed). Six of the seven patients had tumor shrinkage and one had non-measurable disease. All seven assessable patients with MTC experienced a rapid decrease in plasma levels of calcitonin, a marker frequently elevated in MTC, and six of the seven patients had a decrease in the tumor marker carcinoembryonic antigen. All seven MTC patients remain on study. In addition, one patient with a neuroendocrine tumor has an unconfirmed partial response. In total, 15 patients with various malignancies have had stable disease lasting from 3 - 20 months, including nine patients with stable disease for more than six months.
To date, five dose-limiting toxicities (DLTs) have been reported, including Grade 3 palmar/plantar erythema (hand-foot syndrome), Grade 3 AST elevation, Grade 3 ALT elevation, and Grade 3 lipase elevation in patients dosed at 11.52 mg/kg (intermittent dosing schedule), as well as a DLT of Grade 2 mucositis in a patient dosed at 265 mg (daily dosing schedule). Serious adverse events (AEs) considered possibly or probably related to XL184 include one report each of Grade 3 fatigue and Grade 3 pulmonary embolism. Dose escalation continues in order to determine a maximum tolerated dose (MTD).
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XL820, an inhibitor of KIT, VEGFR2, and PDGFR, was the subject of two poster presentations:
Summary of Abstract #B69: XL820 is being evaluated in an ongoing phase 1 trial in patients with metastatic or unresectable solid tumors for which known effective therapeutic measures do not exist or are no longer effective. The study is designed to evaluate five dosing regimens: 200mg, 400mg, 800mg, or 1,600mg dosed once daily (QD), and 300mg dosed twice daily (BID). Twenty-two patients had enrolled in the study as of August 15, 2007. Safety data from 15 patients demonstrate that the compound is generally well tolerated. The most common treatment-related adverse events were nausea, fatigue, diarrhea and vomiting. Dose-limiting toxicities (DLTs) of Grade 3 nausea and Grade 3 fatigue in one patient at 1600 mg QD and in one patient 300 mg BID, respectively, were observed. The maximum tolerated dose (MTD) has not been reached in the BID regimen. There is no evidence that the 300 mg BID cohort (i.e., 600 mg/day) yields a significant difference in cumulative exposure compared to the 400 and 800 mg QQD cohorts (based on limited data).
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Summary of Abstract #B237: : In vitro analyses demonstrate that XL820 is an effective inhibitor of KIT proteins that contain mutations associated with melanoma or with acquired resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GIST). These data support the phase 2 exploration of XL820 in metastatic melanoma and recurrent GIST, cancers that are associated with KIT activation.
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XL844, a potent inhibitor of the checkpoint kinases Chk1 and Chk2, was the subject of one poster presentation:
Summary of Abstract #B228: An analysis of tumor and normal tissue samples indicates that Chk1 and Chk2 RNA and protein are constitutively overexpressed in a variety of tumor tissues compared with normal tissues. In vitro studies demonstrate that XL844 potently inhibits Chk1 and Chk2 and also has activity against VEGFR2, Flt3, Flt4, and PDGFRβ. Studies in a human carcinoma cell line show that addition of chemotherapeutic agents (cisplatin or SN38, the active metabolite of irinotecan) leads to activation of Chk1, Chk2, and cdc2 (another mediator of cell cycling), resulting in cell cycle arrest. XL844 reduces cdc2 phosphorylation in a dose-dependent manner, leading to cell cycle progression. In vivo, administration of XL844 results in durable modulation of cdc2 activity. Cell survival assays show that XL844 potentiates the cytotoxic effects of cisplatin; in tumor models, the combination of XL844 and irinotecan produces a transient but significant inhibition of tumor growth.
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XL518, an inhibitor of MEK1, was the subject of one poster presentation:
Summary of Abstract #C209: In vitro analyses indicate that XL518 is a potent and selective non-competitive inhibitor of MEK1, a component of the Ras/Raf/MEK/ERK signaling pathway. Dysregulation of this pathway contributes to many of the hallmarks of cancer cells: uncontrolled proliferation, invasion, metastasis, angiogenesis, and evasion of apoptosis. Inhibition of MEK activity by XL518 prevents phosphorylation and activation of ERK, thus inhibiting downstream signaling activity. Administration of XL518 results in sustained inhibition of pERK in multiple preclinical tumor models. Notably, pERK inhibition in Colo-205 xenograft tumors is substantially more durable than other MEK inhibitors currently in clinical trials. XL518 shows dose-dependent tumor growth inhibition and regression at well-tolerated doses in multiple preclinical human tumor xenograft models. Based on these data, a Phase 1 trial of XL518 was initiated. This trial is currently enrolling patients with advanced solid malignancies in order to define the maximum tolerated dose as well as pharmacokinetic and pharmacodynamic effects of XL518.
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XL147, an inhibitor of phosphoinositide-3 kinase (PI3K), was the subject of two presentations at the meeting:
Summary of Abstract #C199: XL147 is a potent and selective inhibitor of Class I PI3K lipid kinases. In preclinical studies, XL147 blocks PI3K signaling in tumor cells in vitro, and exhibits dose-dependent and sustained inhibition of PI3K signaling in multiple human tumor xenograft models when administered as a single agent. These xenograft models also show a correlation between XL147 pharmacodynamic activity and increased apoptosis, inhibition of tumor cell proliferation, and inhibition of angiogenesis. Administration of XL147 in combination with various targeted and chemotherapeutic agents results in enhanced anti-tumor efficacy in multiple xenograft models over the corresponding single agents.
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Summary of Abstract #C205: A phase 1 trial of XL147 dosed daily for 21 days in a 28-day cycle is ongoing in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective. As of AACR-NCI-EORTC 2007, no dose limiting toxicities or adverse events related to XL147 have been reported and dose escalation continues. Plasma insulin is being evaluated as a potential circulating biomarker of PI3K inhibition, and potential biomarkers in other tissues are also under evaluation.
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XL765, an inhibitor of PI3K and mammalian target of rapamycin (mTOR), was the subject of two poster presentations:
Summary of Abstract #B250: XL765 is a potent dual inhibitor of both PI3K and mTOR, another component of the PI3K signaling pathway. In preclinical studies, XL765 inhibits PI3K pathway signaling in cellular assays and in xenograft tumor models. In addition, administration of XL765 results in the inhibition of tumor growth and angiogenesis, and of tumor cell survival in xenograft models. XL765 is orally available, exhibits a 24-hour duration of action in pharmacodynamic studies, and is well tolerated at doses that exhibit anti-tumor activity. XL765 also enhances the apoptotic activity of chemotherapeutic agents (paclitaxel or carboplatin) in xenograft tumor models.
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Summary of Abstract #B265: A phase 1 trial of XL765 dosed twice daily is ongoing in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective. No dose limiting toxicities or adverse events related to XL765 were reported in the first two dose cohorts. Additional dose escalation is ongoing. Pharmacodynamic analyses suggest that there is a correlation between XL765 exposure and changes in plasma insulin levels, consistent with inhibition of PI3K. Additional pharmacodynamic studies in blood and hair samples from patients participating in the phase 1 trial are ongoing.
Additional studies are evaluating potential biomarkers of XL765 activity in ex vivo studies in blood and hair samples donated from healthy volunteers. These studies indicate that reductions in the phosphorylation of PI3K pathway targets can be measured, and that these reductions may be used as biomarkers to assess XL765 activity. Additional evaluation of these potential biomarkers is ongoing.
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Investor/Analyst Briefing Back to top
On Wednesday, October 24, 2007, Exelixis held its AACR-NCI-EORTC 2007 investor/analyst briefing, in which senior management reviewed data presented at the conference.
View the archived webcast of the briefing
For investor queries, please contact Charles Butler, Director, Investor Relations: 650-837-7277 or cbutler@exelixis.com
For media queries, please contact Hal Mackins: 650-837-7012 or hmackins@exelixis.com
* - Pursuant to a product development and commercialization agreement between Exelixis and GlaxoSmithKline (GSK), GlaxoSmithKline has the option, after completion of proof-of-concept by Exelixis, to elect to develop up to three compounds in the Exelixis pipeline including XL880, XL784, XL820, XL184, XL844, XL999, XL281, XL418 and XL228.
+ - Out-licensed to Symphony Evolution, Inc. and subject to exclusive repurchase options.
** - XL518 is the subject of a co-development collaboration between Genentech and Exelixis.
