Long-term results in a cohort of medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL184 (BMS 907351), an oral inhibitor of MET, VEGFR2, and RET.
2010; Lippincott Williams & Wilkins; Volume: 28; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2010.28.15_suppl.5502
ISSN1527-7755
AutoresRazelle Kurzrock, Ezra E.W. Cohen, Steven I. Sherman, David G. Pfister, Richard B. Cohen, Douglas W. Ball, David S. Hong, C. S. Ng, Ravi Salgia, Mark J. Ratain,
Tópico(s)Thyroid Cancer Diagnosis and Treatment
Resumo5502 Background: XL184 is an oral inhibitor of MET, VEGFR2, and RET that exhibits anti-angiogenic, antiproliferative, and anti-invasive effects in preclinical models and promising clinical activity in various tumor types in phase I and II trials. MET and RET have been implicated as key factors in the pathobiology of MTC. Methods: Pts with advanced malignancies were enrolled in a phase I dose escalation study of XL184. Primary objectives include safety and pharmacokinetics (PK) and maximum tolerated dose (MTD) determination. RECIST response was assessed on day 28 and every 8 weeks thereafter. Pharmacodynamics, tumor markers, and RET mutational status were analyzed. Adverse events (AEs) and PK results as of 12/2009 are reported. Genotyping and efficacy data are reported for the MTC subgroup (34 of whom are response- assessable). Results: 85 pts were enrolled in this phase I study; the MTD was 175 mg qd. The most frequently occurring possibly related grade 3/4 AEs were fatigue and palmar-plantar erythrodysesthesia (PPE; 10% each); increased lipase (9%); diarrhea (7%); increased amylase (5%); decreased weight and increased AST and ALT (3% each); hypertension and hypocalcemia (2% each). 37 of the 85 pts had a diagnosis of advanced MTC with a minimum follow up period of 17+ months (m). Twenty MTC pts received prior systemic therapy, 16 of whom had prior TKIs (including RET inhibitors). The median duration of response for pts with a cPR has not been reached. Onset of response in 5 pts was rapid with PR reported at the first radiographic evaluation. Ten pts had a confirmed PR (29%, 10/34) and 4 additional pts had at least 30% regression on one scan (total= 41%, 14/34). Fifteen pts (41%, 15/37) had a best response of SD ≥ 6 months. Responses have occurred or been maintained at doses from 75-175 mg. Most MTC pts had reductions in plasma calcitonin and CEA, although these did not correlate with response. Responses have been observed in MTC pts with and without RET mutations. Conclusions: XL184 has demonstrated antitumor activity at and below the MTD. In MTC pts with measurable disease, 29% had a cPR and 68% (25/37) had either cPR or prolonged SD ≥ 6 months. A randomized phase III study in MTC is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Bristol-Myers Squibb, Exelixis
Referência(s)