ASCO 2008

Get information relating to the most current data set presented at the 2008 ASCO annual meeting

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Principal Targets

Preclinical Data

Clinical Data

Information on Clinical Trials

Related Publications

XL647  ²

Stage

Phase 2

Status

Phase 2 trials of XL647 are ongoing for the following:

• Stage IIIB or IV non-small cell lung cancer (NSCLC) patients with confirmed adenocarcinoma histology, who have an activating EGFR mutation or meet at least one of the following clinical criteria: female, of Asian descent, or minimal/never smokers.
• NSCLC in patients who have had disease progression following a previous benefit from erlotinib or gefitinib or who express the T790M mutant form of EGFR.

Indications

NSCLC

Principal Targets

Cell proliferation: EGFR and a variety of mutant forms of EGFR (e.g., T790M), HER2
Angiogenesis (VEGFR)

• EGFR and HER2 are targets for approved cancer therapies.
• Signaling through VEGF/VEGFR2 is the target of approved cancer therapies.
• EGFR is mutationally activated in a subset of NSCLC patients, and some EGFR mutations are associated with resistance to erlotinib and gefitinib.

Preclinical Data

XL647 exhibits potent and sustained inhibition of its key targets in tumor cells following a single oral dose. In a broad array of preclinical tumor models, including breast, lung, colorectal, and prostate cancer, XL647 demonstrated potent inhibition of tumor growth and caused tumor regression. In cell culture and preclinical tumor models, XL647 retains significant potency against mutant EGFRs that are associated with resistance to current EGFR inhibitors such as erlotinib. In addition, XL647 retains activity against a broad spectrum of HER2/ErbB2 mutants that are resistant to lapatinib.

Clinical Data

Data from a phase 2 trial of XL647 were presented most recently at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007.

This open-label phase 2 trial is evaluating XL647 as first-line therapy for previously untreated patients with stage IIIB or IV NSCLC who have adenocarcinoma histology, have an activating EGFR mutation, or meet one of the following three criteria: Asian descent, female gender, or no or minimal smoking history. XL647 is administered orally, at a dose of 350 mg on Days 1-5 of repeated 14-day cycles, or at a dose of 300 mg daily.

As of September 28, 2007, 37 patients had been enrolled in the trial and 32 were evaluable for safety and 34 were evaluable for tumor response assessments.

• 10 of 34 evaluable patients (~30%) experienced partial responses.
  • Patients with and without mutations responded to XL647: 5 had EGFR exon 19 deletions, 1 had an L858R mutation, 3 were wild type, and 1 had pending mutational analysis.
• All patients who had EGFR activating mutations (n=7) experienced clinical benefit.
  • Six patients experienced partial response: 5 had exon 19 deletions and 1 had an L858R mutation.
  • One patient with an L585R mutation experienced stable disease.

View the poster

XL647 was generally well tolerated in this patient population. The most frequently reported adverse events assessed as being related to XL647 were diarrhea, rash, fatigue, and nausea, all of which were Grade 1 or Grade 2 in severity.

• Clinically asymptomatic QTc interval prolongation was observed using machine-read ECGs:
  • Manual re-reading of ECGs generally resulted in lower QTc values.

Data from a phase 1 dose-escalation study evaluating daily dosing of XL647 also were presented at the 2007 AACR-NCI-EORTC meeting. As of September 27, 2007, 26 patients had been enrolled in the trial, with 24 evaluable for safety and 21 evaluable for tumor response assessments. Investigators reported that:

• Eleven 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 maximum tolerated dose in this study was 300 mg.
• Three dose-limiting toxicities occurred:
  • One grade 3 pneumonitis (300 mg): cohort was expanded to 6 patients and no further dose-limiting toxicities were observed.
  • Two grade 3 QTc prolongations (350 mg) as assessed by machine-read ECGs.
    • These events were assessed as Grade 2 following subsequent manual re-reads.
• The most common treatment-related adverse events were Grade 1 and 2 diarrhea, rash, fatigue, and clinically asymptomatic QTc interval prolongation.
• Once-daily administration of 300 mg XL647 is predicted to yield an approximately 2-fold increase in average exposure over a 28-day cycle versus intermittent 5 and 9 dosing with 350 mg.
• Both of the regimens are generally well tolerated.

View the poster

Data from clinical trials of XL647 were previously presented at a variety of venues, including the International Association for the Study of Lung Cancer's 12th World Conference on the Disease in September 2007 and the 43rd Annual Meeting of the American Society of Clinical Oncology in June 2007.

Information on Clinical Trials

Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.

Related Publications

For publication information related to this compound, please see the Related Publications page.

Footnotes:
2 Out-licensed to Symphony Evolution, Inc. and subject to a repurchase option.