Long-term data demonstrates clinical benefits of Exelixis XL184 for medullary thyroid cancer

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Exelixis, Inc. (NASDAQ:EXEL) today reported long-term results in a cohort of 37 medullary thyroid cancer (MTC) patients who participated in the phase 1 study of XL184. Dr. Razelle Kurzrock from the MD Anderson Cancer Center in Houston, TX will present the data in a Clinical Science Symposium (Abstract #5502) on Monday, June 7 at 10:15 AM at the 2010 Annual Meeting of the American Society of Clinical Oncology in Chicago.

“These long-term data demonstrate that XL184 provides clinical benefit to patients with medullary thyroid cancer, and support the ongoing phase 3 pivotal trial of XL184 in this indication”

Thirty-seven of the 85 patients enrolled in the Phase 1 dose-escalation study of XL184 had MTC. Of these 37 patients, 13 were enrolled in the dose escalation portion of the study and 24 were enrolled in the maximum-tolerated dose (MTD) expansion cohort. All 37 patients had metastatic or locally advanced MTC, and patients with familial or sporadic MTC were eligible to participate in the study. Prior therapy was allowed, including treatment with inhibitors of RET, a target of XL184. Thirty-five of 37 MTC patients enrolled in this study had measurable disease by RECIST criteria and were thus evaluable for tumor response, and 34 of these patients had at least one post-baseline tumor assessment.

As of the data cut-off date of April 16, 2010, 10 of 35 patients (29%) with measurable disease had a confirmed partial response (PR) which corresponds to tumor shrinkage of ≥30% on at least two post-baseline scans. Tumor shrinkage ≥30% on at least one post-baseline scan was observed in 17 of the 34 assessable patients (50%). The median time to response was 49.5 days (range of 21- 365 days). Responses appear to be independent of RET mutational status or prior therapy with other RET or VEGFR targeted agents. The median duration of response has not yet been reached with a range of 4 to 35+ months. Fifteen patients (41%) had stable disease for ≥6 months. With a minimum of at least 20 months of follow-up, 11 patients (30%) were still on study at the time of data cut-off.

"These long-term data demonstrate that XL184 provides clinical benefit to patients with medullary thyroid cancer, and support the ongoing phase 3 pivotal trial of XL184 in this indication," said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. "More than 65% of patients had confirmed partial responses or prolonged stable disease, and these benefits appear to be remarkably durable. Importantly, tumor shrinkage was observed even after failure of other targeted therapies, including patients previously treated with vandetanib. We are very encouraged by these results and are optimistic that they will be confirmed in the ongoing XL184 pivotal study."

Adverse events were mostly grade 1 or 2 and were manageable. Most frequently occurring grade 3/4 adverse events included increased pancreatic enzymes (26%), diarrhea (21%), palmar-plantar erythrodysaesthesia (21%), fatigue (16%), increased transaminases (8%), decreased weight (8%), nausea, decreased appetite, vomiting, and hemorrhage (3% each). Grade 3/4 adverse events related to VEGF inhibition included hemorrhage (3%), hypertension (5%), proteinuria (3%), venous thrombosis (5%), peri-rectal/rectal abscess (6%), enterocutaneous fistula (3%) and fistula (3%).

Of 31 patients with known RET status, 25 had known activating mutations in tumors, 3 of which also had activating germline mutations. Most of these patients (15/25) had the M918T RET mutation. Analysis of calcitonin levels revealed substantial decreases in most patients. Changes in calcitonin were rapid, and were observed regardless of prior therapy with other tyrosine kinase inhibitors. Pharmacokinetic analyses indicate a half-life for XL184 of approximately 100 hours, with no significant differences in exposure between patients with MTC and patients with other types of cancer in the phase 1 study.

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