Annual Meeting Proceedings Part 1 - American Society of Clinical ...

636s Sarcoma
10024 Poster Discussion Session (Board #16), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Cetuximab and EGFR inhibitors in patients with neurological symptoms
due to chordoma. Presenting Author: Ola Linden, Department of Oncology,
Lund University Hospital, Lund, Sweden
Background: Chordomas are rare tumours located along the neuraxis,
showing limited sensitivity to radiotherapy and lack of response to chemotherapy.
However, tyrosine kinase inhibitors (TKIs) have been reported to
have an effect. Following the failure of single-agent treatment in a young
patient using cetuximab, we decided to treat patients (pts) with neurological
symptoms with dual targeting of the epidermal growth factor receptor
(EGFR), based on a case report by Hof et al., who successfully used dual
targeting of EGFR, and supporting in vitro data. Methods: Eight consecutive
pts with neurological symptoms at referral were treated with cetuximab
(250 mg/m2 weekly) and an EGFR signalling inhibitor (250 mg gefitinib or
150 mg erlotinib daily). The duration of treatment was not decided in
advance. Results: EGFR expression on tumour cells was variable but
present in all pts. Six pts were evaluable. One tetraplaegic pt died of an
unknown cause and one pt on lithium carbonate discontinued treatment
before the first follow-up due to renal toxicity. Four pts showed neurological
improvement. Two of these regained and one improved the ability to walk,
and a fourth, with a sacral tumour, improved his voiding ability. The fifth pt
had clinically stable disease and, although the PET scan showed improvement,
the treatment had to be discontinued due to skin toxicity. One pt
showed progressive disease. In the four pts responding neurologically,
improvement was noted already by the end of the third week. Three pts were
retreated without failure while on treatment. The first pt who regained the
ability to walk is still walking at 52� months. This pt, while still responsive
to cetuximab and erlotinib, has failed to respond to single-agent treatment
with imatinib, sorafenib or everolimus. The second pt who regained walking
ability had severe alcoholism and died while being treated. The third is still
walking at 16� months. All pts exhibited significant cutaneous side
effects, in some cases necessitating intermittent interruption of therapy.
Conclusions: Treatment with cetuximab and TKIs can thus achieve meaningful
and long-lasting clinical improvement in pts with paresis due to
chordoma, and is feasible in pts with limited comorbidities.
10026 Poster Discussion Session (Board #18), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Lapatinib in advanced chordoma: A phase II study. Presenting Author:
Silvia Stacchiotti, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan,
Italy
Background: To report on a prospective Phase II, investigator-driven,
collaborative study to explore the activity of lapatinib, a dual EGFR and
ErbB2 inhibitor, in EGFR-positive advanced chordomas. Methods: From
December 2009 to December 2011, 19 advanced progressing chordoma
patients entered this study (mean age: 59 yrs – range � 35-75; PS: 0-3 -
�2 � 52%; site: sacrum � 68%, spine � 21%, skull base � 11%; disease
extent: metastatic � 68%, locally advanced � 32%). EGFR expression was
evaluated by immunohistochemistry in all patients. EGFR activation was
detected in 15 of 17 evaluable cases by phospho-arrays and/or real-time
PCR and/or fluorescence immunostaining. EGFR FISH analysis showed
high level of gene gain in 4. HerB2 status is under evaluation. Patients
received lapatinib 1500 mg/day (dose intensity in excess of 1250 mg/day),
until progression or toxicity. The primary study end-point was response rate
(RR) as for Choi criteria extended to MRI. Secondary end-points were RR by
RECIST, PFS by Choi, OS, clinical benefit rate (CBR) (CR�PR�SD�6mos),
correlation between EGFR status and response. Results: 16 pts are
evaluable for response (3 too early); 4 patients are still on treatment. 3
patients (19%) had a partial response (PR) and 8 (50%) a stable disease
(SD) as their best Choi response, corresponding to RECIST SD in all cases.
The 3 cases with a PR by Choi had a minor decrease in size; another patient
had a mixed response. The CBR was 19%. Median PFS as for Choi was 5.5
(range � 2-12�) months, with 1 patient being progression-free at 18
months. Toxicity was as expected. In one case treatment was interrupted
due to side effects. No correlation was observed between EGFR expression/
activation and response. Conclusions: This Phase II study showed a modest
activity of lapatinib in chordoma. EGFR expression was not predictive of
response. The clinical relevance of EGFR targeting in chordoma needs to be
further investigated.
10025 Poster Discussion Session (Board #17), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Establishment of a chordoma xenograft and in vivo testing of compounds
identified by high-throughput screening. Presenting Author: Matteo Maria
Trucco, The Johns Hopkins University, Baltimore, MD
Background: Chordoma is a rare primary bone malignancy that arises in the
skull base, spine and sacrum and originates from remnants of the
notochord. Therapy primarily consists of surgical resection and radiation.
These tumors are typically resistant to conventional chemotherapy, and to
date there are no FDA-approved agents for chordoma. The lack of in vivo
models of chordoma has impeded the development of new therapies for this
tumor. Methods: Primary tumor from a classic sacral chordoma was
obtained, immediately processed into a single cell suspension and injected
in to the parasacral area of a NOD/SCID/IL-2R gamma-null mouse, and
tumor grew after 3 months. The NIH Chemical Genomics Center performed
high-throughput screening of 2,816 compounds. Two established chordoma
cell lines, U-CH1 and UCH2B, were treated and cell viability
measured by CellTiter-Glo assay. Cells were incubated for 48 hours with
drug concentrations ranging from 0.5nM to 46uM. The screen yielded
several compounds that showed activity and two were tested in the
xenograft. Results: We have established a xenograft model of dedifferentiated
chordoma. High-throughput screening of compounds identified compounds
that show activity against chordoma cell lines. In vivo testing of two
identified compounds showed a dramatic reduction of tumor growth.
Conclusions: We have established a xenograft model of dedifferentiated
chordoma. High-throughput screening of compounds identified compounds
that show activity against chordoma cell lines. In vivo testing of two
identified compounds showed a dramatic reduction of tumor growth.
10027 Poster Discussion Session (Board #19), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase
inhibitor (HDACi), in patients (pts) with advanced, previously treated soft
tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French
Sarcoma Group. Presenting Author: Philippe Alexandre Cassier, Centre
Léon Bérard, Lyon, France
Background: Treatment options are limited for pts with advanced pretreated
STS. HDACi have shown activity in preclinical models of STS and SCT
Methods: Pts with advanced pretreated STS and SCT were enrolled in this
open label, single arm, multicenter phase II study. Panobinostat was given
orally, 40 mg thrice per week. The primary end-point was 3-month
progression-free rate according to RECIST 1.1 using central review.
Fleming-A’Hern single-stage design for phase II trials was used, and
assuming a type I error alpha of 5% with 90% power, 15/47 pts were
needed to be progression free at 3 months to reject a rate of 20%. Results:
Fifty three pts were enrolled between January 2010 and January 2011.
Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13
had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had
metastatic disease. The most common sites were the lung and the liver. All
but one pt had documented disease progression prior to study entry. The
median number of prior lines of therapy was 2 (range 1-7). Panobinostat
dose was lowered to 20 mg thrice a week after 11 pts were enrolled based
on the recommendation of an independent safety committee. Fifty-two pts
were evaluable for toxicity (1 pt never received treatment), 48 pts (92%)
reported at least one adverse event (AE) and 22 (42%) reported at least one
treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were
thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the
primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free
at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS
and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two
patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best
response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2
with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1
with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40
mg thrice a week. Efficacy in unselected advanced STS was limited
although some patients had prolonged SD. Activity in pts with SCT warrants
further investigation.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.