Very promising new ASPS treatment (ARQ197,Tavantinib)

[Bonni Hess]

Dear ASPS Community Friends,
Dr. Sawyer, Brittany's very dedicated and knowledgeable Clinical Trial oncologist, thoughtfully wrote us to share the following information about a promising new treatment for ASPS patients called Tavantinib. The Tavantinib study results were co-authored by Dr. John Goldberg who was the lead researcher for the GVAX Immunotherapy Clinical Trial which Brittany participated in at Dana Farber in 2006, and Dr. Goldberg is now continuing his dedicated ASPS research at the University of Miami in Florida. I encourage everyone to read the entire report as it contains some very important and encouraging information about this possible new systemic treatment option for ASPS patients. I Hope that this will provide those of you who are seeking a new treatment a new option for you to explore and to discuss with your oncologist.
With special caring thoughts and continued Hope,
Bonni

Extended Progression-Free Survival in Two
Patients With Alveolar Soft Part Sarcoma
Exposed to Tivantinib
Introduction
Alveolar soft part sarcoma (ASPS) is a rare malignancy that tends
to strike young adults and adolescents. It has an unusual clinical
behavior; it is somewhat indolent, with slow progression, and yet is
incurable once metastasized. Patients with ASPS often present with
extensive metastatic disease, frequently involving the lungs and sometimes
the brain.1-2 On the basis of functional data linking the characteristic
translocation found in ASPS, ASPL-TFE3, to upregulation of
expression of the MET receptor tyrosine kinase,3,4 we proposed to
conduct a clinical trial of tivantinib, an orally available, selective inhibitor
of MET, for patients with ASPS and other cancers with expression
of MET. This was a phase II study with response as the primary
outcome (A Phase II Study ofARQ197 in Patients With Microphthalmia
Transcription Factor Associated Tumors).5 Herein we report two
young patients from this trial who have continued on therapy for
more than 3 years each, with stable disease and minimal adverse
effects, despite metastases at study entry. During the time of the trial,
the study dose of tivantinib was increased from 120 mg twice a day to
360 mg twice a day, on the basis of ongoing parallel pharmacokinetic
studies. The study was Institutional Review Board approved at each
institution where these patients were treated. The consent process for
these minors included obtaining the appropriate assent from the patient
and informed consent from the parents.
Case Report 1
Apreviously well 15-year-old girl was diagnosed withASPSof the
left lateral thigh in January 2007, 1.2 years before study entry. Her
disease was widely metastatic to the lungs at diagnosis. She was initially
treated in 2007 with resection of the thigh mass followed by radiation
of 59.8 Gy to the tumor bed. Later in 2007, she underwent resection of
a tumor nodule in her right lung. She began treatment with sorafenib
in December 2007 and stopped taking it in March 2008, having developed
progressive disease in the lungs during this time.Herleg mass has
never recurred.
After giving informed consent, the patient commenced taking
tivantinib in April 2008 at a dose of 120 mg twice a day. The dose was
escalated to 240 mg twice a day in October 2008, then to 360 mg twice
a day in November 2008, after the amendment to the protocol to
increase the dose was approved at her treating institution. She continues
to receive tivantinib as of January 2013. The drug was temporarily
interrupted for 4 days in May 2008 because of grade 2 hyperbilirubinemia,
which resolved. This patient had no baseline measureable
lesions (waiver granted before enrollment) and her disease at study
entry was comprised of several pulmonary nodules. These have been
stable. She has been taking tivantinib continuously, save for the interruption
described, for 248 weeks as of January 2013. During this time,
the initial clinical trial onto which she was enrolled was closed because
it met accrual requirements, and she continued to receive the study
agent by being rolled over to a follow-up protocol for patients who
experienced benefit associated with tivantinib administration.
Case Report 2
A 12-year-old boy, who had no significant past medical history,
presented to his pediatrician with a lump in his left thigh in July 2007.
Evaluation demonstratednoevidence of bone or brain metastases, but
numerous, bilateral lung nodules were noted on the initial chest computed
tomography (CT) scan. A biopsy that was performed of the
thigh tumor in August 2007 demonstrated ASPS. The patient was
otherwise doing well, and he denied any symptoms aside from the leg
mass. He received initial local control of the left thigh lesion that
consisted of preoperative radiation therapy of 50.4 Gy. In October
2007, surgery was performed, with complete excision of the thigh
mass, which again demonstrated ASPS on pathologic examination,
A B C
Fig 1.
JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y
VOLUME 32 NUMBER 34 DECEMBER 1 2014
e114 © 2014 by American Society of Clinical Oncology Journal of Clinical Oncology, Vol 32, No 34 (December 1), 2014: pp e114-e116
from 198.161.230.10
Information downloaded from jco.ascopubs.org and provided by at CROSS CANCER INSTITUTE on November 27, 2014
Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
with extensive vascular invasion and tumoral thrombosis. There were
numerous satellite nodules around the border of the main mass.
Chemotherapy was not administered to the patient at that time.
A CT scan in late 2008 continued to show numerous lung nodules,
and the patient began a course of 600 mg of imatinib once a day
from October 2008 through January 2009, when he had another CT
scan. This showed an increase in the size of the previously reported
nodules and the presence of new pulmonary nodules. He stopped
imatinib therapy at that time. In March 2009, now 13 years old, he
began tivantinib as part of a study at a dose of 360 mg twice a day after
giving informed consent. A target lesion in the left upper lobe was
identified and is shown in Figures 1A (at study entry), 1B (initial
evaluation at 8 weeks), and 1C (evaluation after 3 years), and has been
observed since. A right lower-lobe pleural-based lesion has been also
been observed (Figs 2A, 2B, and 2C). Despite variability owing to poor
inspiration in the first CT and growth of the patient throughout
treatment, the images suggest stable disease. Since March 2009, he has
received tivantinib at a dose of 360 mg twice every day, through the
writing of this report,andsufferednoadverse events.Hehasgrown5.4
cm in height during this time, to 179 cm, and has completed puberty.
CTscans of his lungs were initially performed every 2monthsandnow
are performed every 4 months. Review of these numerous images
demonstrates no progressionwhenall slices are compared.Hehas had
no demonstrable progression of disease for more than 3 years; all lung
lesions are stable in size and there has been no development of new
lesions. His leg mass has also never recurred. He has also been transitioned
to the follow-up protocol, like the patient described in Case
Report 1. He has been receiving tivantinib for 199 weeks continuously
as of January 2013.
Discussion
The two patients described have both had extended progressionfree
survival in association with exposure to tivantinib. These patient
cases demonstrate the typical, widespread nature of lung metastases in
ASPS. Although ASPS is known to grow slowly, both patients experienced
disease progression during previous therapy. Tivantinib is a
selective inhibitor forMET,with little cross reactivity to other receptor
tyrosine kinases.METis known to be expressed in ASPS.6-7 Immunohistochemistry
forMETwas negative in the tumor samples from both
patients. This may be a result of problems in tissue preservation in the
specimens, which were not obtained specifically for the study, and the
tumors from these patients may in fact be MET dependent and MET
expressing. However, it is possible that these specimens did not express
high levels of MET but were still dependent on MET as a trigger
for the angiogenic behavior that is characteristic of these tumors, given
thatMETactivity can stimulate the vascular endothelial growth factor
receptor (VEGFR) pathway through upregulation of VEGF secretion
and downregulation of thrombospondin-1.8 Antiangiogenic therapy
has been associated with responses in ASPS and is under active development,
although sorafenib was not of benefit in the first patient
described. Sorafenib only impairs VEGF signaling through inhibition
of VEGFR2, which may not have been a sufficient angiogenic blockade
to affect the patient’s tumor. Cediranib has been the most promising
of antiangiogenic agents in ASPS, with a high response rate in
ASPS reported after exposure to this pan-VEGFR inhibitor.9-11 It is
possible that by impairing MET activity, even when the MET activity
was at a low level, tivantinib impaired VEGFR activity in the lung
metastases of these patients and prevented tumor growth as a result.
Many of the patients with ASPS who benefitted from cediranib had
tumor shrinkage while receiving the agent, whereas the two patients
presented here had prolonged stable disease after progression during
previous therapy. This suggests a different mechanism of action on
angiogenesis in ASPS, or at least a different magnitude of effect, from
tivantinib versus cediranib. Another possibility is that inhibition of
MET activity led to inhibition of phosphatidylinositol 3-kinase and
other pathways that are known to be downstream in some models of
oncogenic MET.12 Given the tolerability to tivantinib in these two
patients, further consideration of the agent in select cases of ASPS or in
combination is warranted, particularly if combined with a VEGFR
inhibitor such as cediranib.
John M. Goldberg, Tara Gavcovich, and Gaurav Saigal
University of Miami Miller School of Medicine, Miami, FL
Jonathan W. Goldman and Lee S. Rosen
University of California, Los Angeles, Los Angeles, CA
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
A B C
Fig 2.
Diagnosis in Oncology
http://www.jco.org © 2014 by American Society of Clinical Oncology e115
from 198.161.230.10
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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: None Stock Ownership: None Honoraria: None Research
Funding: John M. Goldberg, ArQule; Jonathan W. Goldman, ArQule;
Lee S. Rosen, ArQule Expert Testimony: None Patents: None Other
Remuneration: None
REFERENCES
1. Ogose A, Yazawa Y, Ueda T, et al: Alveolar soft part sarcoma in Japan:
Multi-institutional study of 57 patients from the Japanese Musculoskeletal
Oncology Group. Oncology 65:7-13, 2003
2. Reichardt P, Lindner T, Pink D, et al: Chemotherapy in alveolar soft part
sarcomas: What do we know? Eur J Cancer 39:1511-1516, 2003
3. Ladanyi M, Lui MY, Antonescu CR, et al: The der(17)t(X;17)(p11;q25) of
human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to
ASPL, a novel gene at 17q25. Oncogene 20:48-57, 2001
4. Tsuda M, Davis IJ, Argani P, et al: TFE3 fusions activate MET signaling by
transcriptional up-regulation, defining another class of tumors as candidates for
therapeutic MET inhibition. Cancer Res 67:919-929, 2007
5. Wagner AJ, Goldberg JM, Dubois SG, et al: Tivantinib (ARQ 197), a
selective inhibitor of MET, in patients with microphthalmia transcription factorassociated
tumors: Results of a multicenter phase 2 trial. Cancer 118:5894-5902,
2012
6. Rosen L, Garcia A, Mulay M, et al: A phase 1 dose escalation study of ARQ
197, a selective inhibitor of the cMet receptor in patients with metastatic solid
tumors. Eur J Cancer 4:196, 2006 (suppl; abstr 651)
7. Jun HJ, Lee J, Lim do H, et al: Expression of MET in alveolar soft part
sarcoma. Med Oncol 27:459-465, 2010
8. Zhang YW, Su Y, Volpert OV, et al: Hepatocyte growth factor/scatter factor
mediates angiogenesis through positive VEGF and negative thrombospondin 1
regulation. Proc Natl Acad Sci U S A 100:12718-12723, 2003
9. Azizi AA, Haberler C, Czech T, et al: Vascular-endothelial-growth-factor
(VEGF) expression and possible response to angiogenesis inhibitor bevacizumab
in metastatic alveolar soft part sarcoma. Lancet Oncol 7:521-523, 2006
10. Balasubramanian L, Evens AM: Targeting angiogenesis for the treatment
of sarcoma. Curr Opin Oncol 18:354-359, 2006
11. Kummar AS, Strassberger A, Monks A, et al: An evaluation of cediranib as
a new agent for alveolar soft part sarcoma (ASPS). J Clin Oncol 29:605s, 2011
(suppl; abstr 10001)
12. Matsumura A, Kubota T, Taiyoh H, et al: HGF regulates VEGF expression
via the c-Met receptor downstream pathways, PI3K/Akt, MAPK and STAT3, in
CT26 murine cells. Int J Oncol 42:535-542, 2013
DOI: 10.1200/JCO.2013.48.7462; published online ahead of print at

[Olga]

Bonni,
we have a discussion re. ARQ197 clinical trial here:
http://www.cureasps.org/forum/viewtopic.php?f=27&t=979
where I recently posted this article. You have probably been away at that time and have not seen it.
ARQ197 is now called Tavantinib, but I am not sure if we can call it "a treatment", is it approved by the FDA yet or it is still in the clinical trial?

[Bonni Hess]

Hi Olga,
You are correct that I somehow missed your November 27th posting of the same article in the Clinical Trial section as I was away from the computer for several days sharing time together with visiting family during the Thanksgiving holiday, and I was unaware until now that ARQ-197 is now called Tavantinib. However, in clicking on the link that you provided it repeatedly says that the content of the article is not currently available so in case other people have experienced the same problem, I think that it is still beneficial to have the entire text of the article posted here. Dr. Sawyer was especially interested in the theory expressed in the article that "further consideration of the agent in select cases of ASPS or in combination is warranted, particularly if combined with a VEGFR inhibitor such as cediranib." The proposed combination of two different targeted anti-angiogenic drugs to gain greater and more sustained effectiveness seems to be gaining more interest in the research community and I will be closely following the development and implementation of this theory for treatment of ASPS and holding very tight to Hope that it proves to be successful.
With special caring thoughts and continued Hope,
Bonni

[Olga]

Yes, Bonni, it is beneficial to post full abstracts here as the links sometimes expire and do not shown an article anymore. I also found it intriguing that part that Dr.Dr. Sawyer pointed at - using these drugs in combination or consequence might alter the ability of the tumor to escape. Do I remember correctly that Brittany had been participating in the ARQ trial for awhile but without response? Could that be that the tumors make up was changed by the ARQ and that made them more susceptible to cediranib...Just speculating.