HGS-ETR2 - A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2006

Presenter: A. Patanaik
Presenter's Affiliation: Cancer Therapy and Research Center, San Antonio, TX
Type of Session: Scientific

Background

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 Methods

Phase 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

Results

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
Pharmacokinetics:
Dose dependent and linear, two-compartment model that shows distribution into tissues
half-life was 11 days
No antibodies against lexatumumab were detected.

Author's Conclusions

Lexatumumab can be safely administered every 2 weeks up to 10 mg/kg. Responses were not overwhelming, and combination studies with chemotherapy are warranted.

Clinical/Scientific Implications

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