Press Release
Press Release
Exelixis and BMS Report Phase 2 Data to Be Presented at ASCO for XL184 in Patients with Previously Treated Glioblastoma Multiforme
XL184 is an orally administered small molecule inhibitor of receptor tyrosine kinases including MET, VEGFR2, and RET. Overexpression of MET and VEGFR2, as well as the ligands which activate these receptors, has been shown to correlate with poor prognosis in GBM, which is the most common and aggressive form of brain tumor. In addition, phosphorylated RET has been described in some cases of GBM.
The exploratory study is evaluating the safety, tolerability and clinical activity of XL184 at a continuous daily dose of 175 mg in patients with previously treated GBM. To date, 46 patients who make up the intent to treat (ITT) population have been enrolled in the trial, including 30 (65%) in first relapse and 16 (35%) in second or third relapse. Importantly, the trial did not exclude patients previously treated with an antiangiogenic agent.
Tumor response, as determined by an independent radiology facility (IRF), using MacDonald criteria were reported. By ITT analysis, 7 of 35 (20%) of the antiangiogenic naïve patients had a confirmed partial response. The overall rate of response in all patients, including the refractory population of previously treated patients with an antiangiogenic therapy, was 15%. The median duration of response by IRF was 2.9 months (range = 1.9-8.6 months). In an exploratory analysis, among 35 patients with at least one post baseline MRI scan, 12 (34%) had tumor shrinkage ≥50% as their best response as determined by investigator, including 1 patient who had received prior antiangiogenic therapy.
The efficacy evaluable population was defined as patients having received at least 1 dose of XL184 and either had at least 1 post-baseline tumor assessment per investigator or failed to return for any tumor assessments because of death or clinical determination of progression. In the anti-angiogenic naïve population, 7 of 31 (23%) of efficacy evaluable patients had a confirmed partial response by IRF. The 6-month progression-free survival (PFS) rate in patients receiving no prior antiangiogenic therapy was 23%, with 10 patients censored for PFS at the time of analysis, and the median PFS interval was 3.6 months.
“These initial data from our ongoing GBM program are encouraging, and
suggest that XL184 could have utility in this underserved indication,”
said
All 46 patients were evaluated for safety. Most adverse events were of Grade 1 or 2 severity. The most frequently occurring Grade 3 and Grade 4 adverse events were: fatigue (30%), alanine aminotransferase increase (9%), confusional state (9%), lipase increase (9%), lymphopenia (9%), convulsion (7%), headache (7%), and hypophosphatemia (7%). Adverse events of special interest were: hypertension (all incidences, 39%; Grade 3/4, 7%), palmar-plantar erythrodysesthesia (30%; 7%), bleeding events (28%; 9%), proteinuria (26%; 0%), pulmonary embolism (9%; 7%) and craniotomy wound dehiscence (4%; 2%).
In the study, 87% of patients had a dose interruption of XL184, median average daily dose was 122 mg/day. XL184 will be evaluated at a lower dose of 125 mg daily in order to provide continuous and sustained exposure to the drug in this previously treated glioblastoma population.
Correlative tumor profiling and biomarker evaluation and vascular
imaging data from this trial will also be presented in two additional
posters in the same poster session. Abstract 2048, entitled
“Neurovascular imaging in GBM patients quantifies early physiologic
changes after treatment with XL184, an inhibitor of multiple receptor
tyrosine kinases: results from a Phase 2 study” will be presented by
About XL184
XL184 (BMS-907351) is a small molecule designed to inhibit MET, VEGFR2,
and RET. MET is a receptor tyrosine kinase that plays a key role in
cellular proliferation, migration, and angiogenesis. These biological
processes contribute to the transformation, progression, survival, and
metastasis of cancer cells. MET is mutationally activated in some tumor
types, such as hereditary and sporadic papillary renal cell carcinoma
and some head and neck cancers. More frequently, MET is either
over-expressed or activated in the absence of mutation in glioblastomas,
breast carcinomas, some gastric cancers, and other solid tumors. MET
amplification has been demonstrated in some NSCLCs. Expression of VEGF
has been observed in a variety of cancers and has been associated with
prognostic significance. Targeting the VEGF receptor has been recognized
as a potential anti-cancer strategy in multiple tumors. Dual targeting
of MET and VEGFR2 blocks two of the major mechanisms tumors use to
overcome hypoxia. Activated RET is involved in cell signaling cascades
that regulate cell proliferation, migration, differentiation, and
survival. RET is mutationally activated in papillary thyroid cancer
(PTC) and in both familial and sporadic forms of medullary thyroid
cancer (MTC).
About
About
Exelixis Forward-Looking Statements
This press release contains forward-looking statements by
Source:
Bristol-Myers Squibb Company
Brian Henry, 609-252-3337
Director,
Business Communications
brian.henry@bms.com
or
Exelixis,
Inc.
Charles Butler, 650-837-7277
Executive Director,
Corporate Communications & Investor Relations
cbutler@exelixis.com