HGS-ETR2 - A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de junio de 2006
Presenter: A. Patanaik
Presenter's Affiliation: Cancer Therapy and Research Center, San Antonio, TX
Type of Session: Scientific
- Death receptors, such as TNF-alpha receptor, Fas, and TRAIL-R (TNF-alpha Related Apoptosis Inducing Ligand Receptor)-1 and –2, can stimulate the extrinsic apoptotic pathway in tumor cells when activated by their cognate ligands
- Stimulation of TNF-alpha receptor and Fas have been associated with unacceptable systemic toxicities, limiting the clinical utility of targeting these pathways. In contrast, pre-clinical data has shown that stimulation of the TRAIL receptor can selectively kill tumor cells without systemic toxicity
- There are two human TRAIL receptors: TRAIL-R1 (DR4) and TRAIL-R2 (DR5).
- Lexatumumab (HGS-ETR2) is a fully humanized monoclonal agonistic antibody to TRAIL-R2.
- Lexatumumab has been studied in a Phase I study in the UK, with Grade 3 dose limiting toxicities (DLT's) occurring in 1 patient at the 1 mg/kg level and 3 patients at the 20 mg/kg level
- This was an open-label, two-center Phase I study of lexatumumab in patients with incurable solid tumors
Materials and MethodsPhase I study design:
- 31 patients with advanced solid tumors
- Dose escalation: 0.1, 0.3, 1, 3, 10 mg/kg i.v. administered every 2 weeks until tumor progression or unacceptable toxicity
- Toxicity, pharmacokinetics, immunogenicity and best responses were assessed
- Tumors were measured every 2 months
- 167 courses were given to 31 patients, median = 4 courses
- One patient has continued treatment for over a year
- No Grade 3 DLT's observed in first 4 dose cohorts.
- One patient in the 10 mg/mL cohort had Grade 3 hyperamylasemia, however this patient had a Grade 2 baseline elevation and this normalized after dose. Incidentally, this patient was taking supplement with mushroom extract.
- Most of the observed toxicities were Grade 1/2 fatigue, nausea, pain, and anorexia that would be expected in the heavily pre-treated group of patients
- Best responses:
- Stable disease in 10 patients for 4 to 16 cycles
- Mixed response (shrinkage and progression of different lesions) in one patient with refractory Hodgkin's disease
- Dose dependent and linear, two-compartment model that shows distribution into tissues
- half-life was 11 days
- No antibodies against lexatumumab were detected.
- Lexatumumab can be safely administered every 2 weeks up to 10 mg/kg. Responses were not overwhelming, and combination studies with chemotherapy are warranted.
- This confirms the UK Phase I trial (ETR2-ST01) that lexatumumab can be safely administered in doses up to 10 mg/kg. The primary difference in this trial was that lexatumumab was given every 2 weeks instead of every 3 weeks.
- Serum amylase levels should be monitored closely in patients receiving lexatumumab
- The long half-life (11 days) is potentially advantageous compared with the pharmacokinetics of the native ligand, TRAIL (half-life=0.6 hr). The selective activation of only TRAIL-R2 (DR5) is a potential disadvantage compared to TRAIL, which can activate both isoforms.
- The underwhelming overall response rates, especially from an agent that supposedly induces apoptosis, indicates that the TRAIL pathway will likely require combination therapy. Which agents to combine with TRAIL receptor-activating agents, however, remains an important unanswered question