Ali, Siraj M.

Frampton, Garrett M.

Lee, Carrie

McMahon, Caitlin

Usenko, Dimitry

Weiss, Jared

Carrie Lee

Dimitry Usenko

Garrett M. Frampton

Caitlin McMahon

Siraj M. Ali

Jared Weiss

Crossref

Journal of Thoracic Oncology

MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor

Carolina Digital Repository

e113Journal of Thoracic Oncology ® • Volume 10, Number 12, December 2015The patient is a 61-year-old male never smoker who first presented with pain in his left hip and right-sided chest pain in 2014. Imaging revealed lytic bone lesions in the left iliac wing, right sixth rib, left eleventh rib, and T12. Core biopsy was performed on the left iliac wing, and it revealed CK7+, TTF1+, and vimentin+ sarcomatoid non–small-cell lung cancer. Comprehensive genomic profiling was per-formed through FoundationOne (Foundation Medicine, Inc., Cambridge, MA) on the pretreatment biopsy specimen, and the tumor harbored two MET alterations predicted to result in skipping of exon 14 (c.2888-5_2890TTAAGATC>A and c.3028+2T>G) and a known activating point mutation in MET (p.H1094Y, c.3280C>T).The patient was treated with radiation to painful bony lesions followed by carboplatin, paclitaxel, and bevacizumab on the ECOG5508 trial (NCT01107626). Although there was some evidence for response after two cycles, he experienced clear progressive disease after four cycles and MET-directed therapy was considered.Skipping of exon 14 deletes a region of the juxtamem-brane domain causing a decreased rate of MET degradation. Mutations leading to MET exon 14 skipping have previously been reported including responses to MET inhibitors.1–3 In light of the multiple MET alterations observed in the patient including an activating mutation, he was treated on a clini-cal trial of the MET inhibitor crizotinib (NCT00585195). He experienced a partial response by Response Evaluation Criteria in Solid Tumors 1.0 criteria, which was accompanied by the patient reporting symptomatic improvement in activ-ity level and pain. Most notably, a dominant right-sided chest mass decreased from 8.2 to 6.1 cm, but there was no clear change in bony lesions (Fig. 1). This lasted for more than 5 months until he experienced progressive pain. Imaging con-firmed progression both in the lung and in bony lesions. The patient is now on hospice care.This case illustrates the potential of comprehensive genomic profiling to identify mutations that are actionable on clinical trials and the potential activity of crizotinib against MET exon 14 splice site mutations, a hypothesis being tested by ongoing studies (NCT00585195). Such findings will be applicable to a sizable group of patients—MET mutations have been estimated to occur in 3% of squamous cell cancers of the lung4 and 3–8% of adenocarcinomas of the lung1,5 as well as in other lung neoplasms, brain gliomas, and cancers of unknown primary.1REfERENCES 1. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015;8: 850–859. 2. Jenkins RW, Oxnard GR, Elkin S, Sullivan EK, Carter JL, Barbie DA. Response to crizotinib in a patient with lung adenocarcinoma harbor-ing a MET splice site mutation. Clin Lung Cancer 2015 [Epub ahead of print]. 3. Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842–849. 4. Cancer Genome Atlas Research Network. Comprehensive genomic char-acterization of squamous cell lung cancers. Nature 2012;489:519–25. 5. Cancer Genome Atlas Research Network. Comprehensive molecular pro-filing of lung adenocarcinoma. Nature 2014;511: 543–50.DOI: 10.1097/JTO.0000000000000645Copyright © 2015 by the International Association for the Study of Lung CancerISSN: 1556-0864/15/1012-e113*Division of Hematology and Oncology, Linberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, North Carolina; and †Research and Development, ‡Clinical Bioinformatics Operations, and §Clinical Development, Foundation Medicine Inc., Cambridge, Massachusetts.Disclosure: Dr. Lee, Dr. Usenko, and Dr. Weiss report that UNC received support for participation in clinical trial NCT00585195. Dr. Frampton, Caitlin McMahon, and Dr. Ali report employment with Foundation Medicine and have equity interest in Foundation Medicine.Address for correspondence: Jared Weiss, MD, 170 Manning Drive, Room 3115, Campus Box 7305, Chapel Hill, NC 27599.E-mail: jared_weiss@med.unc.eduMET 14 Deletion in Sarcomatoid Non–Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET InhibitorCarrie Lee, MD,* Dimitry Usenko, MD,* Garrett M. Frampton, PhD,† Caitlin McMahon,†  Siraj M. Ali, MD, PhD,§ and Jared Weiss, MD*XXXCASE REPORTe114 Copyright © 2015 by the International Association for the Study of Lung CancerLee et al Journal of Thoracic Oncology ® • Volume 10, Number 12, December 2015fIGURE 1. Pre- and post treatment CT scans.

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e113Journal of Thoracic Oncology ® • Volume 10, Number 12, December 2015
The patient is a 61-year-old male never smoker who ﬁrst presented with pain in his left hip and right-sided chest 
pain in 2014. Imaging revealed lytic bone lesions in the left 
iliac wing, right sixth rib, left eleventh rib, and T12. Core 
biopsy was performed on the left iliac wing, and it revealed 
CK7+, TTF1+, and vimentin+ sarcomatoid non–small-cell 
lung cancer. Comprehensive genomic proﬁling was per-
formed through FoundationOne (Foundation Medicine, Inc., 
Cambridge, MA) on the pretreatment biopsy specimen, and 
the tumor harbored two MET alterations predicted to result 
in skipping of exon 14 (c.2888-5_2890TTAAGATC>A and 
c.3028+2T>G) and a known activating point mutation in MET 
(p.H1094Y, c.3280C>T).
The patient was treated with radiation to painful bony 
lesions followed by carboplatin, paclitaxel, and bevacizumab 
on the ECOG5508 trial (NCT01107626). Although there was 
some evidence for response after two cycles, he experienced 
clear progressive disease after four cycles and MET-directed 
therapy was considered.
Skipping of exon 14 deletes a region of the juxtamem-
brane domain causing a decreased rate of MET degradation. 
Mutations leading to MET exon 14 skipping have previously 
been reported including responses to MET inhibitors.1–3 In 
light of the multiple MET alterations observed in the patient 
including an activating mutation, he was treated on a clini-
cal trial of the MET inhibitor crizotinib (NCT00585195). 
He experienced a partial response by Response Evaluation 
Criteria in Solid Tumors 1.0 criteria, which was accompanied 
by the patient reporting symptomatic improvement in activ-
ity level and pain. Most notably, a dominant right-sided chest 
mass decreased from 8.2 to 6.1 cm, but there was no clear 
change in bony lesions (Fig. 1). This lasted for more than 5 
months until he experienced progressive pain. Imaging con-
ﬁrmed progression both in the lung and in bony lesions. The 
patient is now on hospice care.
This case illustrates the potential of comprehensive 
genomic proﬁling to identify mutations that are actionable on 
clinical trials and the potential activity of crizotinib against 
MET exon 14 splice site mutations, a hypothesis being tested 
by ongoing studies (NCT00585195). Such ﬁndings will be 
applicable to a sizable group of patients—MET mutations 
have been estimated to occur in 3% of squamous cell cancers 
of the lung4 and 3–8% of adenocarcinomas of the lung1,5 as 
well as in other lung neoplasms, brain gliomas, and cancers of 
unknown primary.1
REfERENCES
 1. Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via 
diverse exon 14 splicing alterations occurs in multiple tumor types and 
confers clinical sensitivity to MET inhibitors. Cancer Discov 2015;8: 
850–859.
 2. Jenkins RW, Oxnard GR, Elkin S, Sullivan EK, Carter JL, Barbie DA. 
Response to crizotinib in a patient with lung adenocarcinoma harbor-
ing a MET splice site mutation. Clin Lung Cancer 2015 [Epub ahead 
of print].
 3. Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients 
with stage IV lung adenocarcinomas harboring MET mutations causing 
exon 14 skipping. Cancer Discov 2015;5:842–849.
 4. Cancer Genome Atlas Research Network. Comprehensive genomic char-
acterization of squamous cell lung cancers. Nature 2012;489:519–25.
 5. Cancer Genome Atlas Research Network. Comprehensive molecular pro-
ﬁling of lung adenocarcinoma. Nature 2014;511: 543–50.
DOI: 10.1097/JTO.0000000000000645
Copyright © 2015 by the International Association for the Study of Lung 
Cancer
ISSN: 1556-0864/15/1012-e113
*Division of Hematology and Oncology, Linberger Comprehensive Cancer 
Center at the University of North Carolina, Chapel Hill, North Carolina; 
and †Research and Development, ‡Clinical Bioinformatics Operations, 
and §Clinical Development, Foundation Medicine Inc., Cambridge, 
Massachusetts.
Disclosure: Dr. Lee, Dr. Usenko, and Dr. Weiss report that UNC received 
support for participation in clinical trial NCT00585195. Dr. Frampton, 
Caitlin McMahon, and Dr. Ali report employment with Foundation 
Medicine and have equity interest in Foundation Medicine.
Address for correspondence: Jared Weiss, MD, 170 Manning Drive, Room 
3115, Campus Box 7305, Chapel Hill, NC 27599.E-mail: jared_weiss@
med.unc.edu
MET 14 Deletion in Sarcomatoid Non–Small-Cell Lung 
Cancer Detected by Next-Generation Sequencing and 
Successfully Treated with a MET Inhibitor
Carrie Lee, MD,* Dimitry Usenko, MD,* Garrett M. Frampton, PhD,† Caitlin McMahon,†  
Siraj M. Ali, MD, PhD,§ and Jared Weiss, MD*
XXX
CASE REPORT
e114 Copyright © 2015 by the International Association for the Study of Lung Cancer
Lee et al Journal of Thoracic Oncology ® • Volume 10, Number 12, December 2015
fIGURE 1. Pre- and post treatment CT scans.


MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor 

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MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor

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