|
|
Phase II study of erlotinib in
recurrent GBM: Molecular predictors of outcome
T. Cloughesy, A.
Yung, J. Vrendenberg, K. Aldape, D.
Eberhard, M. Prados, S. Vandenberg, B.
Klencke and P. Mischel
UCLA, Los Angeles, CA; M.D.
Anderson, Houston, TX; Duke, Durham, NC; M.D. Anderson Cancer Ctr,
Houston, TX; Genentech, San Francisco, CA; UCSF, San Francisco, CA
Background. Erlotinib
(Tarceva) is an orally active, highly potent and selective
inhibitor of the epidermal growth factor receptor
(EGFR).
Preliminary results from this phase II trial of erlotinib
for GBM in first relapse have been reported (ASCO 2004,
Abs#1555).
Updated clinical results and molecular characterization of
archival tissue samples are now available.
Methods. A
multi-institutional phase II clinical trial of single agent
erlotinib until disease progression enrolled GBM patients
with measurable disease in first relapse.
Individual dose titration until dose-limiting toxicity
(diarrhea, rash, other) was allowed in 2 dose cohorts: patients
taking enzyme-inducing anti-epileptic drugs or not.
Subjects were evaluated for response every 8 weeks.
Submission of archival tissue was mandatory.
Depending on the amount of tissue available, the following
assays were performed: EGFR amplification by FISH (Vysis);
and EGFR, EGFRvIII (Zymed) and PTEN expression by
IHC.
Results. Forty-eight
subjects (19 female, 29 male) with a median age of 51 years
(37–73) were enrolled over 3 months from 4 centers.
The investigator determined response rate (WHO criteria)
was 8.4% (3 PR, 1CR), with SD as the best response in 37.5%
(n=18).
One SD patient who died of an MI at day 84 had only
microscopic foci of viable tumor amidst significant necrosis
on autopsy.
The 6 month PFS rate was 17% and median survival was 10
months.
Tissue is missing from 1 PR with the longest ongoing
response.
EGFRvIII analysis is ongoing.
Conclusions. Erlotinib
is active in recurrent GBM, with a promising response rate,
6 m PFS and median survival.
Molecular analyses show a slight trend towards better
outcome with EGFR expression however, the differences are
not significant due to the small numbers.
|
EGFR FISH
|
EGFR IHC
|
PTEN IHC
|
|
+
n=23
|
- or Unknw
n=25
|
+
n=15
|
-
n=20
|
WT
n=23
|
Loss
n=14
|
|
CR+PR
|
8.7%
|
8.0%
|
13.3%
|
5.0%
|
13.0%
|
0%
|
|
CR+PR+SD
|
56.5%
|
36.0%
|
66.7%*
|
35.0%*
|
47.8%
|
50.0%
|
|
6 month PFS
|
19.6%
|
14.6%
|
23.3%*
|
10.0%*
|
13.0%
|
19.0%
|
|
*The negative category for
FISH includes 1 PR without tissue.
*P-values 0.09 for each comparison
|
|
