VOLUME 36 • NUMBER 14 • MAY 10, 2018

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Phase II Study of Crizotinib in East Asian Patients With

ROS1-Positive Advanced Non–Small-Cell Lung Cancer
Yi-Long Wu, James Chih-Hsin Yang, Dong-Wan Kim, Shun Lu, Jianying Zhou, Takashi Seto, Jin-Ji Yang, Noboru
Yamamoto, Myung-Ju Ahn, Toshiaki Takahashi, Takeharu Yamanaka, Allison Kemner, Debasish Roychowdhury,
Jolanda Paolini, Tiziana Usari, Keith D. Wilner, and Koichi Goto

Author affiliations and support information

(if applicable) appear at the end of this A B S T R A C T
article.
Purpose
Published at jco.org on March 29, 2018.
Approximately 1% to 2% of non–small-cell lung cancers (NSCLCs) harbor a c-ros oncogene 1 (ROS1)
Clinical trial information: NCT01945021. rearrangement. Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and MET, has
Corresponding author: Yi-Long Wu, MD, shown marked antitumor activity in a small expansion cohort of patients with ROS1-positive ad-
Guangdong Lung Cancer Institute, 106 vanced NSCLC from an ongoing phase I study. We assessed the efficacy and safety of crizotinib in
Zhongshan Er Rd, Guangzhou 510080,
China; e-mail: [email protected].
the largest cohort of patients with ROS1-positive advanced NSCLC.
© 2018 by American Society of Clinical Patients and Methods
Oncology This phase II, open-label, single-arm trial enrolled East Asian patients with ROS1-positive (assessed
0732-183X/18/3614w-1405w/$20.00 through validated AmoyDx assay [Amoy Diagnostics, Xiamen, China] at three regional laboratories)
advanced NSCLC who had received three or fewer lines of prior systemic therapies. Patients were to
receive oral crizotinib at a starting dose of 250 mg twice daily and continued treatment until Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1–defined progression (by independent radiology
review [IRR]), unacceptable toxicity, or withdrawal of consent. The primary end point was objective
response rate (ORR) by IRR.
Results
In the efficacy and safety analyses, 127 patients were included, with 49.6% still receiving treatment
at data cutoff. ORR by IRR was 71.7% (95% CI, 63.0% to 79.3%), with 17 complete responses and
74 partial responses. ORRs were similar irrespective of the number of prior lines of therapy, and
responses were durable (median duration of response, 19.7 months; 95% CI, 14.1 months to not
reached). Median progression-free survival by IRR was 15.9 months (95% CI, 12.9 to 24.0 months).
No new safety signals associated with crizotinib were reported.
Conclusion
This study demonstrated clinically meaningful benefit and durable responses with crizotinib in East
Asian patients with ROS1-positive advanced NSCLC. Crizotinib was generally well tolerated, with
a safety profile consistent with previous reports.

J Clin Oncol 36:1405-1411. © 2018 by American Society of Clinical Oncology

This oncogenicity has been described in a variety

INTRODUCTION
of cancer types, including glioblastoma,3 gastric
cancer,4 cholangiocarcinoma,5 ovarian cancer,6
The c-ros oncogene 1 (ROS1) encodes for an and non–small-cell lung cancer (NSCLC).7
orphan receptor tyrosine kinase from the insulin Approximately 1% to 2% of patients with
receptor family that is related to anaplastic NSCLC harbor an ROS1 rearrangement, with
lymphoma kinase (ALK) and leukocyte receptor approximately 15,000 of the 1.5 million new cases
tyrosine kinase.1 Chromosomal rearrangements of NSCLC each year believed to be driven by
that involve the ROS1 gene lead to fusion of oncogenic ROS1 fusions.2,8-10 The incidence is
ASSOCIATED CONTENT
a portion of ROS1 that contains a tyrosine kinase slightly higher in the East Asian population at
Appendix
DOI: https://doi.org/10.1200/JCO.
domain with one of several partner proteins.2 The a frequency of 2% to 3%.11 Although patients
2017.75.5587 resulting ROS1 fusion kinases are constitutively with ROS1-positive NSCLC have similar char-
DOI: https://doi.org/10.1200/JCO.2017. activated and trigger growth and survival sig- acteristics to those with ALK-positive NSCLC (ie,
75.5587 naling pathways that drive cellular proliferation.2 young in age, adenocarcinoma histology, and

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 Wu et al

positive for the ROS1 fusion gene. Crizotinib was approved in

Table 1. Baseline Patient Characteristics and Demographics
adults with ROS1-positive advanced NSCLC in the European
Total, Japan, China, Other,* Union in August 2016 and has been approved in . 45 countries
Characteristic No. (%) No. (%) No. (%) No. (%)
worldwide, including China and Japan. We report the results from
No. of patients 127 26 74 27
a large, ongoing phase II trial that has been assessing the efficacy
Age, years
Median 51.5 56.3 49.5 52.7 and safety of crizotinib in East Asian patients with ROS1-rearranged
Range 22.8-79.7 30.2-79.1 22.8-79.7 33.8-73.8 advanced NSCLC.
Age group
, 65 years 106 (83.5) 17 (65.4) 65 (87.8) 24 (88.9)
$ 65 years 21 (16.5) 9 (34.6) 9 (12.2) 3 (11.1)
Sex PATIENTS AND METHODS
Male 54 (42.5) 10 (38.5) 34 (45.9) 10 (37.0)
Female 73 (57.5) 16 (61.5) 40 (54.1) 17 (63.0)
Patients
Smoking history
No 91 (71.7) 16 (61.5) 55 (74.3) 20 (74.1)
Eligible patients were $ 18 years of age with histologically or cy-
Yes 36 (28.3) 10 (38.5) 19 (25.7) 7 (25.9) tologically confirmed locally advanced or metastatic NSCLC that was
ECOG PS at baseline positive for ROS1 rearrangements and negative for ALK rearrangements.
0 34 (26.8) 10 (38.5) 9 (12.2) 15 (55.6) Positivity for ROS1 rearrangements was determined using a reverse
1 93 (73.2) 16 (61.5) 65 (87.8) 12 (44.4) transcription-polymerase chain reaction (RT-PCR) assay (AmoyDx; Amoy
Histologic classification Diagnostics, Xiamen, China) performed by three regional laboratories.
Adenocarcinoma 124 (97.6) 26 (100.0) 71 (95.9) 27 (100.0) Fourteen ROS1 fusion genes are detectable by the AmoyDx assay (Ap-
Squamous cell carcinoma 1 (0.8) 0 (0.0) 1 (1.4) 0 (0.0) pendix Table A1, online only). The test configuration is conducted in tubes
Large-cell carcinoma 2 (1.6) 0 (0.0) 2 (2.7) 0 (0.0)
because the sample must be split among the reactions. Thus, the assay is
Extent of disease
not configured to report individual variant-specific positivity. Using the
Locally advanced only 6 (4.7) 0 (0.0) 4 (5.4) 2 (7.4)
Metastatic 121 (95.3) 26 (100.0) 70 (94.6) 25 (92.6)
same assay performed at a designated central laboratory, a nationwide
Brain metastases at genomic screening network in Japan (LC-SCRUM-Japan) contributed to
baseline† screening eligible ROS1-positive patients. ALK negativity was confirmed
Yes 23 (18.1) 3 (11.5) 12 (16.2) 8 (29.6) by one of three locally approved tests, that is, AmoyDx RT-PCR, immu-
No. of prior regimens for nohistochemistry (Ventana Medical Systems, Oro Valley, AZ), or Vysis
advanced disease fluorescence in situ hybridization (FISH) test (Abbott Laboratories,
0 24 (18.9) 2 (7.7) 18 (24.3) 4 (14.8)
Chicago, IL). Other eligibility criteria included three or fewer lines of prior
1 53 (41.7) 14 (53.8) 27 (36.5) 12 (44.5)
2 31 (24.4) 6 (23.1) 17 (21.6) 8 (29.6)
systemic therapies for advanced-stage disease, one or more measurable
3 19 (15.0) 4 (15.4) 12 (17.6) 3 (11.1) tumor lesions (as assessed by Response Evaluation Criteria in Solid Tu-
mors [RECIST] version 1.1) that were not irradiated, and an Eastern Co-
Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance operative Oncology Group (ECOG) performance status (PS) of 0 or 1.
status. Patients with brain metastases were eligible if asymptomatic or were
*Includes patients enrolled in South Korea and Taiwan.
†By independent radiology review. neurologically stable for $ 2 weeks if treated. Prior therapy directed against
ALK or ROS1 was not permitted. All patients provided informed consent.

Study Design and Treatment

nonsmoker status), ROS1 and ALK rearrangements are considered to This ongoing, open-label, multinational, single-arm, multicenter
be mutually exclusive; therefore, both define a distinct molecular phase II clinical trial was performed at 37 sites across East Asia. The study
subset of NSCLC.12 began in September 2013, and the cutoff date for this analysis was July 30,
Crizotinib is a first-in-class, oral, small-molecule tyrosine 2016. The institutional review board or independent ethics committee at
kinase inhibitor (TKI) of ALK, mesenchymal–epithelial transition/ each participating center approved the protocol, which complied with the
hepatocyte growth factor receptor (MET), and ROS1 kinases.13,14 International Ethical Guidelines for Biomedical Research Involving Hu-
man Subjects, Good Clinical Practice Guidelines, the Declaration of
Preclinical experiments have shown that cell lines with ROS1
Helsinki, and local laws.
rearrangement are sensitive to inhibition of ROS1 kinase, which Patients were to be administered oral crizotinib at a starting dose of
suggests a use for targeted therapy.14 Crizotinib showed marked 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles.
antitumor activity, with an objective response rate (ORR) of 69.8% Treatment continued until RECIST-defined disease progression (de-
in an expansion cohort of 53 patients with ROS1-positive NSCLC termined by independent radiology review [IRR]), unacceptable toxicity,
from the phase I Safety, Pharmacokinetic and Pharmacodynamic or withdrawal of consent. At the investigator’s discretion, patients could
Study of PF-02341066 (crizotinib), a cMET/Hgfr Selective Tyrosine continue treatment beyond RECIST-defined progression if they had on-
going clinical benefit. The primary end point was ORR by IRR. Secondary
Kinase Inhibitor, Administered Orally to Patients With Advanced
efficacy end points were duration of response (DOR), time to first tumor
Cancer, (PROFILE 1001).15 Results from a retrospective cohort response (TTR), disease control rate (DCR), progression-free survival
study and preliminary results from two prospective phase II (PFS), and overall survival (OS). Safety and patient-reported outcomes
studies, all conducted in Europe, also have presented notable (PROs) also were assessed.
clinical activity of crizotinib against ROS1-positive lung can-
cer.16-18 On the basis of the results from the phase I expansion
Study Assessments
cohort in April 2015, the US Food and Drug Administration Tumor assessments were performed at baseline, every 8 weeks until
granted breakthrough therapy designation to crizotinib for the cycle 8, and every 12 weeks thereafter until disease progression by IRR or
ROS1 indication and in March 2016, approved crizotinib for the treatment discontinuation. Brain and bone scans were to be performed at
treatment of patients with metastatic NSCLC whose tumors are screening; if lesions were present at baseline, repeat scans were to be taken

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 Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

every 8 (brain) or 12 (bone) weeks. All images were subject to review by an

independent radiology laboratory, and tumor responses were assessed Table 2. Summary of Efficacy End Points
using RECIST version 1.1. End Point Total, No. (%)
Adverse events (AEs) were classified and graded according to Na-
No. of patients 127
tional Cancer Institute Common Terminology Criteria for Adverse Events Best overall response*
(version 4.03). PROs for disease and treatment-related symptoms, func- Complete response 17 (13.4)
tioning, and global quality of life (QOL) were assessed by the European Partial response 74 (58.3)
Organization for Research and Treatment of Cancer (EORTC) Core Stable disease 21 (16.5)
Quality of Life Questionnaire (QLQ-C30) and the corresponding Lung Progressive disease 9 (7.1)
Cancer Module (QLQ-LC13). Early death† 2 (1.6)
Indeterminate 4 (3.1)
ORR* 91 (71.7)
Statistical Analysis 95% CI‡ 63.0 to 79.3
An ORR of 30% was considered a clinically meaningful threshold for TTR, months*
this study, and a lower limit of the two-sided 95% CI around the observed Median 1.9
ORR greater than this threshold would demonstrate the efficacy of cri- Range 1.6 to 15.8
DOR, months*§
zotinib. By assuming a 50% true ORR, the statistical power to demonstrate
Median 19.7
efficacy on the basis of this threshold was 98.2% with 100 evaluable 95% CI 14.1 to NR
patients; the 95% CI for an observed ORR of 50% is 40% to 60%. A total of DCR, %*
110 patients were projected to be enrolled. Week 8 (95% CI)‡ 88.2 (81.3 to 93.2)
The safety analysis population included all enrolled patients who Week 16 (95% CI)‡ 80.3 (72.3 to 86.8)
received at least one dose of crizotinib; the response-evaluable population PFS*§, months
was defined as all patients in the safety analysis population who had an Median 15.9
adequate baseline tumor assessment. ORR (percentage of patients with 95% CI 12.9 to 24.0
a best overall response of a confirmed complete or confirmed partial Survival probabilityk, %
Month 6 (95% CI) 92.0 (85.7 to 95.6)
response) and DCR (percentage of patients with a confirmed complete or
Month 12 (95% CI) 83.1 (75.2 to 88.6)
confirmed partial response or stable disease) by IRR were evaluated in the
Overall survival§, months
response-evaluable population, and the 95% CIs were calculated using the Median 32.5
exact method on the basis of the F-distribution. 95% CI 32.5 to NR
DOR was summarized by Kaplan-Meier method and descriptive
statistics; TTR was summarized using descriptive statistics only. DOR and Abbreviations: DCR, disease control rate; DOR, duration of response; NR, not
reached; ORR, objective response rate; PFS, progression-free survival; TTR, time
TTR were assessed only in the subgroup of responder-patients in the
to first tumor response.
response-evaluable population. *By independent radiology review.
In the safety analysis population, the Kaplan-Meier method was used †Death within 42 days of first dose; grade 5 respiratory failure, not related
to estimate median PFS and OS; two-sided 95% CIs are provided. PRO end to treatment (n = 1); and grade 5 pneumonia, not related to treatment (n = 1).
‡Calculated using the exact method on the basis of F-distribution.
points were analyzed in the PRO-evaluable population (all patients in the
§Kaplan-Meier estimate.
safety analysis population who completed a baseline and one or more kKaplan-Meier estimate calculated using the log-cumulative hazard transformation.
post–baseline PRO assessments). Changes in EORTC QLQ-C30 and QLQ-
LC13 scores of $ 10 points from baseline were considered clinically
meaningful19 and statistically significant if the 95% CIs did not include 0.
For summary purposes, PRO results are presented in detail for the first 20
cycles because later cycles had a smaller number of patients at the time of
enrollment country, age, sex, smoking status, or ECOG PS
data cutoff, which limited data interpretation. (Table 3). Objective responses were rapid in onset, with a median
TTR of 1.9 months (range, 1.6 to 15.8 months), which coincided
with the first on-treatment tumor assessment. Responses also
RESULTS were durable (median DOR, 19.7 months; 95% CI, 14.1 months
to not reached [NR]). The DCR was maintained in 88.2% of
Patients patients (95% CI, 81.3% to 93.2%) at week 8 and 80.3% of
patients (95% CI, 72.3% to 86.8%) at week 16 (Table 2). Of the 63
Between September 2013 and January 2015, 127 patients with
patients who experienced disease progression while being treated
ROS1-positive NSCLC were enrolled at 37 sites in China, Japan,
with crizotinib, 43 (68.3%) continued treatment with crizotinib
South Korea, and Taiwan and received one or more doses of
for $ 3 weeks postprogression (median duration, 20.7 weeks;
crizotinib. Baseline characteristics for this study population are
range, 3.3 to 92.7).
listed in Table 1. All patients included in this study were Asian, with
Median PFS was 15.9 months (95% CI, 12.9 to 24.0 months;
most from China (58.3%) and Japan (20.5%).
Fig 2), and 45 (35.4%) of 127 patients were still in follow-up for
PFS at data cutoff. In patients with (n = 23) and without (n = 104)
Efficacy baseline brain metastases, median PFS was 10.2 months (95% CI,
ORR by IRR was 71.7% (95% CI, 63.0% to 79.3%), with 17 5.6 to 13.1 months) and 18.8 months (95% CI, 13.1 months to
patients achieving a complete response and 74 patients achieving NR), respectively. However, this finding should be interpreted with
a partial response (Table 2; Fig 1). ORR met the prospectively caution because of the small sample size of patients with baseline
defined clinically meaningful threshold for this study with the brain metastases. Median duration of follow-up for OS was
lower bound of the two-sided 95% CI . 30% (Table 2). This 21.4 months (95% CI, 20.1 to 23.0 months). Median OS was
clinical benefit was observed irrespective of the presence of brain 32.5 months (95% CI, 32.5 months to NR); however, 59.8% of
metastases at baseline, number of prior lines of chemotherapy, patients were still in follow-up at data cutoff, so OS data are

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 Wu et al

50

40
Complete response (n = 17)
30 Partial response (n = 74)
Change in Target Lesions From Baseline (%)

Stable disease (n = 18)

20
Progressive disease (n = 7)
10

–10

–20

–30

–40

–50

–60

–70

–80

–90

–100

Fig 1. Best percent change in the target tumor burden from baseline as assessed by independent radiology review. Number of patients is based on the response-
evaluable population that excludes early death, indeterminate, and patients with nontarget lesions only.

considered to be immature. Probabilities of survival were 92.0% PROs

(95% CI, 85.7% to 95.6%) and 83.1% (95% CI, 75.2% to 88.6%) at During the first 20 treatment cycles, almost all patients (99% to
6 and 12 months, respectively (Table 2). 100%) completed at least one question from the EORTC QLQ-C30

Safety Table 3. Independent Radiology Review–Assessed ORR by Baseline

Characteristics
At the data cutoff, median duration of crizotinib treatment
Total Crizotinib (N = 127)
was 18.4 months (range, 0.1 to 34.1 months), and 63 patients
(49.6%) were still receiving crizotinib. The safety profile of cri- No. of
Characteristic Patients ORR, % (95% CI)
zotinib in this study was consistent with previous reports.20,21
Country
Treatment-related AEs (TRAEs), most of which were grade 1 or 2
China 53 of 74 71.6 (59.9 to 81.5)
in severity, occurred in 96.1% of patients (Table 4). The most Japan 17 of 26 65.4 (44.3 to 82.8)
frequently reported TRAEs of any grade were elevated trans- Other 21 of 27 77.8 (57.7 to 91.4)
aminases (55.1%), vision disorder (48.0%), nausea (40.9%), di- Sex
Male 34 of 54 63.0 (48.7 to 75.7)
arrhea (38.6%), and vomiting (32.3%).
Female 57 of 73 78.1 (66.9 to 86.9)
Overall, grade 3 or 4 events related to crizotinib were reported Age-group
in 32 patients (25.2%). The most common grade 3 or 4 TRAEs , 65 years 78 of 106 73.6 (64.1 to 81.7)
were neutropenia and elevated transaminases, which occurred in $ 65 years 13 of 21 61.9 (38.4 to 81.9)
Smoking history
10.2% and 5.5% of patients, respectively. One patient (0.8%) No 68 of 91 74.7 (64.5 to 83.3)
permanently discontinued crizotinib in association with a grade 1 Yes 23 of 36 63.9 (46.2 to 79.2)
TRAE (diarrhea). Dose reductions and dosing interruptions as- Baseline ECOG PS
sociated with TRAEs were reported in 15.7% and 22.8% of pa- 0 24 of 34 70.6 (52.5 to 84.9)
1 67 of 93 72.0 (61.8 to 80.9)
tients, respectively. Brain metastases at baseline
By the time of data cutoff, 39 patients (30.7%) had died during Yes 17 of 23 73.9 (51.6 to 89.8)
the study. The most common cause was disease progression in 35 No 74 of 104 71.2 (61.4 to 79.6)
No. of prior regimens for advanced
patients (27.6%). Other causes were pneumonia in two patients disease
(1.6%), respiratory failure in one patient (0.8%), and unknown in ,2 56 of 77 72.7 (61.4 to 82.3)
one patient (0.8%). No cases of treatment-related pneumonitis $2 35 of 50 70.0 (55.4 to 82.1)
were reported. Overall, 10 patients (7.9%) had a grade 5 AE Abbreviations: ECOG, Eastern Cooperative Oncology Group; ORR, objective
(disease progression [n = 6], respiratory failure [n = 2], and response rate; PS, performance status.
pneumonia [n = 2]), and none of these were related to crizotinib.

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 Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

100

90

80

70

60
PFS (%)

Median PFS, 15.9 months (95% CI, 12.9 to 24.0 months)

50

40 Fig 2. Progression-free survival (PFS) as

assessed by independent radiology review in
30 the safety analysis population.
20

10

0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
No. at risk:
Crizotinib 127 110 91 78 66 56 46 28 16 7 3 0 0

and QLQ-LC13. In the PRO-evaluable population (n = 123), sta- regardless of demographic or baseline characteristics in line with
tistically significant improvements in global QOL were seen at cycles previous reports. Of note, responses were achieved in patients in-
3 to 5, 7, and 10 (Appendix Fig A1, online only). From cycles 2 to 20, dependent of prior line of therapy, which shows that crizotinib is
most patients had either improved ($ 10 point improvement from beneficial in both first- and later-line settings. Intracranial response
baseline; 30.4% to 37.0%) or stable (, 10 point change from was not assessed and may be considered a limitation of this trial.
baseline; 38.4% to 46.8%) scores in global QOL during therapy. Overall, the current results demonstrate that crizotinib is clinically
Mean change from baseline in patient-reported EORTC QLQ- effective for the treatment of patients with ROS1-positive NSCLC,
C30 scores for insomnia and dyspnea symptoms showed statistically which further confirms the results seen in PROFILE 1001. On the
significant and clinically meaningful improvement ($ 10 points) at basis of these results, crizotinib received approval for ROS1-positive
several time points over the first 20 cycles. Similar improvements were NSCLC in Japan, Taiwan, China, and Korea in 2017.
seen in EORTC QLQ-LC13 scores for patient-reported symptoms of The ability to detect the presence of specific cancer-causing gene
cough (cycles 2 to 8, 10, 12, 14, 16, 18, and 20) and pain in chest rearrangements enables the identification of particular patient pop-
(cycles 16, 18, and 20). Statistically significant improvements were ulations that may benefit most from target therapies. To evaluate
observed in a range of other symptoms, including fatigue (cycles 3 to samples for ROS1 rearrangements, we used an RT-PCR assay
8, 10, 12, 14, 16, 18, and 20), pain (cycles 2 to 8, 10, 12, 14, 16, 18, and
20), and appetite loss (cycles 4 to 6, 8, 12, 14, 16, and 18). A statistically
significant and clinically meaningful deterioration from baseline was Table 4. Treatment-Related Adverse Events in Patients Treated With Crizotinib
observed in some cycles for constipation (cycles 2 to 4, 12, 16, and 18) (n = 127)
and diarrhea (cycles 2 to 8, 10, and 16). All Grades, Grade 3, Grade 4,
Adverse Event No. (%) No. (%)* No. (%)
Any 122 (96.1) 28 (22.0) 4 (3.1)
In $ 10% of patients
DISCUSSION Elevated transaminases† 70 (55.1) 5 (3.9) 2 (1.6)
Vision disorder† 61 (48.0) 0 (0.0) 0 (0.0)
To our knowledge, this study is the first and largest prospective phase Nausea 52 (40.9) 2 (1.6) 0 (0.0)
Diarrhea 49 (38.6) 1 (0.8) 0 (0.0)
II trial in East Asian patients with ROS1-positive advanced NSCLC
Vomiting 41 (32.3) 0 (0.0) 0 (0.0)
in which crizotinib demonstrated robust clinical activity. ORRs by Constipation 38 (29.9) 0 (0.0) 0 (0.0)
IRR were achieved in a high proportion of patients (71.7%; 95% CI, Neutropenia† 37 (29.1) 11 (8.7) 2 (1.6)
63.0 to 79.3), similar to that reported in the expansion cohort of the Leukopenia† 29 (22.8) 3 (2.4) 0 (0.0)
Edema† 29 (22.8) 0 (0.0) 0 (0.0)
single-arm PROFILE 1001 trial (69.8%; 95% CI, 55.7 to 81.7)15 and Dysgeusia 22 (17.3) 0 (0.0) 0 (0.0)
to preliminary ORR results from two prospective European phase II Decreased appetite 20 (15.7) 1 (0.8) 0 (0.0)
trials.17,18 Responses were rapid and generally coincided with the Blood creatinine increased† 19 (15.0) 0 (0.0) 0 (0.0)
first tumor assessments taken at the 8-week point, which were Fatigue 15 (11.8) 1 (0.8) 0 (0.0)
Bradycardia† 13 (10.2) 2 (1.6) 0 (0.0)
similar to PROFILE 1001. The PFS achieved in the current study
(median, 15.9 months) corroborates the long median PFS reported *Other grade 3 treatment-related adverse events in $ 1% of patients were ECG
QT prolonged (1.6%) and renal cyst† (1.6%).
in PROFILE 1001.15 However, surveillance brain magnetic reso- †This item comprised a cluster of adverse events that may represent similar clinical
nance images were not mandated in patients without baseline CNS symptoms or syndromes, which are listed in Appendix Table A2 (online only).
metastases. Evidence of clinical benefit was observed in patients

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 Wu et al

(AmoyDx) designed to detect 14 of the most common ROS1 fusion the time of data cutoff. Secondary mutations that impede drug binding,
genes, which account for the majority of ROS1 rearrangements found in epidermal growth factor receptor activation, and epithelial-to-
lung adenocarcinomas.22 The AmoyDx is approved for use in Japan and mesenchymal transition have been identified as mechanisms of cri-
China and is European conformity marked. FISH, which also requires zotinib resistance.28 In vitro studies have found that cabozantinib,
pathologic interpretation, may also be used to identify patients with a multitargeted TKI, effectively inhibits the survival of cells with
ROS1 gene rearrangements who would likely benefit from targeted acquired crizotinib-resistant ROS1 mutations (eg, G2023R29 and
therapy. This method was predominantly used and performed locally in D2033N30). A marked clinical response to cabozantinib also was ob-
PROFILE 1001.21 Boyle et al23 found that some ROS1 fusion genes, such served in a patient with the D2033N substitution.30 A case study showed
as those that contain the partner protein ezrin (EZR), may not be that a patient with NSCLC with an ERZ-ROS1 fusion gene, who had
detected as efficiently by FISH as other ROS1 rearrangements, which acquired resistance to crizotinib through a dual mutation (S1986Y and
highlights potential consistency issues. In addition to FISH and RT- S1986F), responded to lorlatinib, a next-generation ALK/ROS1 in-
PCR, several methodologies exist for detection of ROS1 fusions. For hibitor.31 Lorlatinib also has shown clinical activity in a small set of
example, Thermo Fisher Scientific (Waltham, MA) has recently re- patients with ROS1-rearranged NSCLC, some of whom had been
ceived approval from the US Food and Drug Administration for a next- previously treated with targeted TKI therapy.32 These findings suggest
generation sequencing–based detection platform that includes ROS1. that sequential therapy may play a role in ROS1-positive NSCLC similar
Other studies have used immunohistochemistry for ROS1 screening, to that observed in patients with ALK positivity. Additional studies that
such as the European trial, AcSé CRIZOTINIB: Secured Access to investigate treatment sequencing may be of interest.
Crizotinib for Patients With Tumors Harboring a Genomic Alteration In conclusion, crizotinib provided meaningful clinical benefit
on One of the Biological Targets of the Drug.17 In previous studies, the in East Asian patients with ROS1-positive advanced NSCLC, with
AmoyDx RT-PCR diagnostic test was successfully used to identify durable clinical responses and improvements in QOL and
ROS1-positive NSCLC with a sensitivity of 100% and a specificity of symptom burden. Results from this study, to our knowledge the
85% to 100%, using FISH as the reference standard method.24,25 The largest phase II trial in ROS1-positive advanced NSCLC to date,
assay used in the current study provides an effective option for provides additional compelling clinical evidence to support the use
identifying patients with ROS1 fusion genes who are likely to benefit of crizotinib in this molecular subgroup of patients with NSCLC.
from ROS1-targeted therapy with crizotinib.
The safety profile of crizotinib reported in this single-arm trial was
consistent with that reported in previous studies in patients with ROS1- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
positive and ALK-positive lung cancers.15,20,26,27 Most AEs reported in OF INTEREST
the current study were of grade 1 or 2 severity, and no grade 5 TRAEs
were observed, which indicates that crizotinib generally was well Disclosures provided by the authors are available with this article at
tolerated. AEs attributed to crizotinib were manageable by dosing jco.org.
interruptions/reductions, with a low rate of permanent treatment
discontinuations associated with TRAEs. Although the frequency of
elevated transaminases and neutropenia seem to be higher in this study AUTHOR CONTRIBUTIONS
than in PROFILE 1001,21 the percentages for the associated laboratory
abnormalities are comparable. Therefore, no new safety signals were Conception and design: Yi-Long Wu, James Chih-Hsin Yang, Dong-Wan
identified in East Asian patients with ROS1-positive NSCLC. Kim, Takashi Seto, Jin-Ji Yang, Takeharu Yamanaka, Allison Kemner, Keith
Symptom burden in patients with advanced lung cancer D. Wilner, Koichi Goto
usually is high, which results in a negatively affected QOL in most Provision of study materials or patients: Yi-Long Wu, James Chih-Hsin
Yang, Dong-Wan Kim, Shun Lu, Jianying Zhou, Myung-Ju Ahn, Koichi
patients. In the current study, a trend toward an improvement in
Goto
patient-reported global QOL and reduction in many patient- Collection and assembly of data: Yi-Long Wu, James Chih-Hsin Yang,
reported lung cancer-related symptoms—several to a clinically Shun Lu, Jianying Zhou, Takashi Seto, Noboru Yamamoto, Myung-Ju Ahn,
meaningful extent—was found. Patients appeared to undergo an Toshiaki Takahashi, Allison Kemner, Debasish Roychowdhury, Keith D.
improvement in lung-related symptoms from the first post– Wilner, Koichi Goto
baseline assessment through the first 20 cycles of treatment. Data analysis and interpretation: Yi-Long Wu, James Chih-Hsin Yang,
However, these PRO data should be considered with caution Dong-Wan Kim, Shun Lu, Noboru Yamamoto, Myung-Ju Ahn, Allison
Kemner, Debasish Roychowdhury, Jolanda Paolini, Tiziana Usari, Keith D.
because of the absence of a comparator arm. Wilner, Koichi Goto
As seen with other targeted therapies for NSCLC, patients with Manuscript writing: All authors
ROS1-positive NSCLC may develop resistance to crizotinib, as evi- Final approval of manuscript: All authors
denced by the 63 of 127 patients who experienced disease progression at Accountable for all aspects of the work: All authors

2. Davies KD, Doebele RC: Molecular pathways: axis to form glioblastoma in mice. Cancer Res 66:
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

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Affiliations
Yi-Long Wu and Jin-Ji Yang, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou; Shun Lu, Jiao
Tong University, Shanghai; Jianying Zhou, First Affiliated Hospital of Zhejiang University, Hangzhou, People’s Republic of China; James
Chih-Hsin Yang, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Republic of China; Dong-
Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center, Seoul, South Korea; Takashi Seto, National
Kyushu Cancer Center, Fukuoka; Noboru Yamamoto, National Cancer Center Hospital, Tokyo; Toshiaki Takahashi, Shizuoka Cancer
Center, Shizuoka; Takeharu Yamanaka, Yokohama City University School of Medicine, Yokohama; Koichi Goto, National Cancer Center
Hospital East, Kashiwa, Japan; Allison Kemner and Debasish Roychowdhury, OxOnc Development, Princeton, NJ; Nirvan Consultants,
Lexington, MA; Jolanda Paolini and Tiziana Usari, Pfizer, Milan, Italy; and Keith D. Wilner, Pfizer, La Jolla, CA.
Support
Supported by OxOnc Development and Pfizer.
Prior Presentation
Presented at the ASCO Annual Meeting, Chicago, IL, June 3-7, 2016; 14th Annual Meeting of the Japanese Society of Medical
Oncology, Kobe, Japan, July 28-30, 2016; 19th Annual Meeting of the Chinese Society of Clinical Oncology, Xiamen, China, September 21-
25, 2016; 57th Annual Meeting of the Japan Lung Cancer Society, Fukuoka, Japan, December 19-21, 2016; and 15th Annual Meeting of the
Japanese Society of Medical Oncology, Kobe, Japan, July 27-29, 2017.

nnn

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 Wu et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non–Small-Cell Lung Cancer
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Yi-Long Wu Myung-Ju Ahn
Honoraria: AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, Sanofi No relationship to disclose
Consulting or Advisory Role: AstraZeneca, Roche, Merck, Boehringer
Ingelheim Toshiaki Takahashi
Research Funding: Boehringer Ingelheim (Inst), Roche (Inst) Honoraria: AstraZeneca, Pfizer, Eli Lilly Japan, Chugai Pharmaceutical,
Ono Pharmaceutical, Nippon Boehringer Ingelheim, MSD
James Chih-Hsin Yang
Honoraria: Boehringer Ingelheim, Roche, Chugai Pharmaceutical, MSD, Takeharu Yamanaka
AstraZeneca, Novartis Honoraria: Chugai Pharmaceutical, Takeda Pharmaceuticals, Taiho
Consulting or Advisory Role: Boehringer Ingelheim, Novartis, Pharmaceutical, Boehringer Ingelheim
AstraZeneca, Roche, Genentech, Eli Lilly, MSD, EMD Serono, Celgene, Consulting or Advisory Role: Gilead Sciences
Astellas Pharma, Bayer AG, Ono Pharmaceutical, Bristol-Myers Squibb, Research Funding: Takeda Pharmaceuticals (Inst), Taiho Pharmaceutical
Boehringer Ingelheim (Inst), AstraZeneca (Inst), Yuhan, Hansoh (Inst)
Pharmaceutical Allison Kemner
Dong-Wan Kim Employment: OxOnc Services, Incyte
No relationship to disclose Stock or Other Ownership: GlaxoSmithKline, Incyte

Shun Lu Debasish Roychowdhury

Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Leadership: OxOnc Development
Hutchison MediPharma, Simcere Pharmaceutical, Roche Stock or Other Ownership: OxOnc Development
Speakers’ Bureau: AstraZeneca, Eli Lilly, Hutchison MediPharma, Roche, Jolanda Paolini
Sanofi Employment: Pfizer
Research Funding: AstraZeneca, Boehringer Ingelheim, Hutchison Stock or Other Ownership: Pfizer
MediPharma, Roche
Tiziana Usari
Jianying Zhou Employment: Pfizer
No relationship to disclose Stock or Other Ownership: Pfizer
Takashi Seto Keith D. Wilner
Honoraria: AstraZeneca KK, Chugai Pharmaceutical, Kyowa Hakko Kirin, Employment: Pfizer
Nippon Boehringer Ingelheim, Nippon Kayaku, Ono Pharmaceutical, Stock or Other Ownership: Pfizer
Bristol-Myers Squibb, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Roche,
Yakult Honsha Koichi Goto
Research Funding: Astellas Pharma (Inst), AstraZeneca KK (Inst), Chugai Honoraria: Daiichi Sankyo, Kyowa Hakko Kirin, Bristol-Myers Squibb,
Pharmaceutical (Inst), EMD Serono (Inst), MSD (Inst), Nippon AstraZeneca, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono
Boehringer Ingelheim (Inst), Novartis (Inst), Pfizer (Inst), Daiichi Sankyo Pharmaceutical, Novartis, Eli Lilly, Boehringer Ingelheim, Quintiles, EMD
(Inst), Eli Lilly Japan (Inst), Eisai (Inst) Serono, SRL, Life Technologies
Consulting or Advisory Role: Chugai Pharmaceutical, Daiichi Sankyo
Jin-Ji Yang Research Funding: MSD, AstraZeneca, Taiho Pharmaceutical, Chugai
No relationship to disclose Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, OxOnc,
Noboru Yamamoto Sumitomo Dainippon Pharma, Takeda Pharmaceuticals, Novartis, Daiichi
Honoraria: AstraZeneca, Pfizer, Chugai Pharmaceutical, Bristol-Myers Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Eli Lilly, Amgen,
Squibb, Ono Pharmaceutical, Eli Lilly Japan Pfizer, Riken Genesis, Bristol-Myers Squibb, EMD Serono, AbbVie
Consulting or Advisory Role: Eisai, Takeda Pharmaceuticals, Otsuka,
Nippon Boehringer Ingelheim
Research Funding: Chugai Pharmaceutical (Inst), Taiho Pharmaceutical
(Inst), Eisai (Inst), Quintiles (Inst), Astellas Pharma (Inst), Novartis (Inst),
Daiichi Sankyo (Inst), Eli Lilly Japan (Inst), Takeda Pharmaceuticals (Inst),
Kyowa Hakko Kirin (Inst), Pfizer (Inst), Ono Pharmaceutical (Inst),
Nippon Boehringer Ingelheim (Inst)

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 Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

Acknowledgment

We thank the patients, families, teams of investigators, research nurses, study coordinators, operations staff, and the Chinese Thoracic
Oncology Group who made this work possible. Medical writing support was provided by Jade Drummond and Simon Lancaster of
inScience Communications, Springer Healthcare (Chester, United Kingdom), and was funded by Pfizer.

Appendix

12
Change From Baseline in Global QOL
Standardized Score, Mean (95% CI)

10

–2

–4
Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 10 Cycle 12 Cycle 14 Cycle 16 Cycle 18 Cycle 20
(n = 122) (n = 115) (n = 112) (n = 108) (n = 105) (n = 99) (n = 96) (n = 89) (n = 81) (n = 79) (n = 70) (n = 70) (n = 68)

Fig A1. Change from baseline in global quality of life (QOL) standardized scores on the basis of the patient-reported outcomes–evaluable population at baseline (cycle 1).
The number of patients who completed the scale at baseline and at respective cycles are shown.

Table A1. ROS1 Fusion Genes Detectable by AmoyDx Assay

Tube No. ROS1 Exon Type of Fusion Gene (Fusion Partner and Exon)
1 32 SLC34A2 exon 4 SLC34A2 exon 14del CD74 exon 6
SDC4 exon 2 SDC4 exon 4 —
2 34 SLC34A2 exon 4 SLC34A2 exon 14del CD74 exon 6
SDC4 exon 4 EZR exon 10 —
3 35 TPM3 exon 8 LRIG3 exon 16 GOPC exon 8
4 36 GOPC exon 4 — —

NOTE. Expected frequencies of fusion partners are as follows: CD74 (42%), EZR (15%), SLC34A2 (12%), SDC4 (7%), GOPC [FIG] (3%), TPM3 (3%), and LRIG3 (1%).12

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 Wu et al

Table A2. Preferred Terms Within Each Clustered Term

Clustered Term Preferred Terms
Abdominal pain Abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness
Anemia Anemia, anemia macrocytic, anemia megaloblastic, hemoglobin, hemoglobin decreased, hyperchromic anemia,
hypochromic anemia, hypoplastic anemia, microcytic anemia, normochromic normocytic anemia
Blood creatinine increased Blood creatinine abnormal, blood creatinine increased, creatinine renal clearance abnormal, creatinine renal
clearance decreased, glomerular filtration rate abnormal, glomerular filtration rate decreased
Blood testosterone decreased Androgen deficiency, blood gonadotropin abnormal, blood gonadotropin decreased, blood gonadotropin increased,
blood testosterone abnormal, blood testosterone decreased, blood testosterone free decreased, gonadotropin
deficiency, hypogonadism, hypogonadism male, saliva testosterone abnormal, saliva testosterone decreased,
secondary hypogonadism
Bradycardia Bradyarrhythmia, bradycardia, heart rate decreased, sinus arrest, sinus bradycardia
Cardiac failure Acute left ventricular failure, acute right ventricular failure, cardiac failure, cardiac failure acute, cardiac failure chronic,
cardiac failure congestive, cardiac failure high output, cardiopulmonary failure, chronic left ventricular failure,
chronic right ventricular failure, ejection fraction decreased, left ventricular failure, pulmonary edema, right
ventricular failure, ventricular failure
Chest pain Chest discomfort, chest pain, musculoskeletal chest pain, noncardiac chest pain
Cholestasis Bilirubin conjugated, bilirubin conjugated abnormal, bilirubin conjugated increased, bilirubin excretion disorder, blood
bilirubin, blood bilirubin abnormal, blood bilirubin increased, cholestasis, cholestatic liver injury, hepatitis
cholestatic, hyperbilirubinemia, jaundice, jaundice cholestatic, jaundice hepatocellular, ocular icterus, yellow skin
Cough Cough, productive cough
Dizziness Balance disorder, dizziness, dizziness exertional, dizziness postural, presyncope
Dyspnea Dyspnea, dyspnea at rest, dyspnea exertional, dyspnea paroxysmal nocturnal, nocturnal dyspnea, orthopnea
Edema Edema, edema peripheral, eye swelling, face edema, generalized edema, local swelling, localized edema, periorbital
edema
Elevated transaminases ALT, ALT abnormal, ALT increased, AST, AST abnormal, AST increased, g-glutamyltransferase abnormal,
g-glutamyltransferase increased, hepatic enzyme abnormal, hepatic enzyme increased, hepatic function
abnormal, hypertransaminasemia, liver function test abnormal, liver function test increased, transaminases,
transaminases abnormal, transaminases increased
Esophagitis Erosive esophagitis, esophageal perforation, esophageal rupture, esophageal ulcer, esophageal ulcer hemorrhage,
esophageal ulcer perforation, esophagitis, esophagitis hemorrhagic, esophagitis ulcerative, necrotizing
esophagitis
GI perforation Anastomotic ulcer perforation; diverticular perforation; duodenal perforation; duodenal ulcer perforation; duodenal
ulcer perforation, obstructive, gastric perforation; gastric ulcer perforation; gastric ulcer perforation, obstructive, GI
anastomotic leak; GI perforation; GI ulcer perforation, ileal perforation; ileal ulcer perforation; intestinal perforation;
intestinal ulcer perforation; jejunal perforation; jejunal ulcer perforation; large intestinal ulcer perforation; large
intestine perforation; peptic ulcer perforation; peptic ulcer perforation, obstructive, perforated peptic ulcer
oversewing; perforated ulcer; rectal perforation; small intestinal perforation; small intestinal ulcer perforation
Hepatotoxicity Acute hepatic failure, cholestatic liver injury, coma hepatic, drug-induced liver injury, hepatic encephalopathy, hepatic
failure, hepatic necrosis, hepatic steatosis, hepatitis fulminant, hepatorenal failure, hepatocellular injury,
hepatorenal syndrome, hepatotoxicity, liver disorder, liver injury, mixed liver injury, subacute hepatic failure
Interstitial lung disease Acute interstitial pneumonitis, acute lung injury, acute respiratory distress syndrome, alveolitis, alveolitis allergic,
alveolitis necrotizing, diffuse alveolar damage, eosinophilic pneumonia, eosinophilic pneumonia acute, idiopathic
pulmonary fibrosis, interstitial lung disease, pneumonitis, pulmonary toxicity
Leukopenia Leukopenia, WBC count decreased
Lymphopenia Lymphocyte count decreased, lymphopenia
Neuropathy Acute polyneuropathy, amyotrophy, areflexia, autoimmune neuropathy, autonomic failure syndrome, autonomic
neuropathy, axonal neuropathy, biopsy peripheral nerve abnormal, burning feet syndrome, burning sensation,
decreased vibratory sense, demyelinating polyneuropathy, dysesthesia, electromyogram abnormal, formication,
gait disturbance, genital hypoesthesia, Guillain-Barré syndrome, hyperesthesia, hypoesthesia, hyporeflexia,
hypotonia, ischemic neuropathy, loss of proprioception, Miller Fisher syndrome, mononeuritis, mononeuropathy,
mononeuropathy multiplex, motor dysfunction, multifocal motor neuropathy, muscle atrophy, muscular
weakness, myelopathy, nerve conduction studies abnormal, nerve degeneration, neuralgia, neuritis,
neuromuscular toxicity, neuromyopathy, neuronal neuropathy, neuropathy peripheral, neuropathy vitamin B6
deficiency, neurotoxicity, paresthesia, peripheral motor neuropathy, peripheral nerve lesion, peripheral nerve
palsy, peripheral nervous system function test abnormal, peripheral sensorimotor neuropathy, peripheral sensory
neuropathy, peroneal nerve palsy, phrenic nerve paralysis, polyneuropathy, polyneuropathy chronic,
polyneuropathy idiopathic progressive, radiation neuropathy, sensorimotor disorder, sensory disturbance, sensory
loss, skin burning sensation, small fiber neuropathy, temperature perception test decreased, Tinel’s sign, toxic
neuropathy, ulnar neuritis
Neutropenia Febrile neutropenia, neutropenia, neutrophil count decreased
Pulmonary embolism Pulmonary artery thrombosis, pulmonary embolism, pulmonary thrombosis
Radiation-induced interstitial lung disease Pulmonary radiation injury, radiation alveolitis, radiation fibrosis–lung, radiation pneumonitis
Renal cyst Renal abscess, renal cyst, renal cyst excision, renal cyst hemorrhage, renal cyst infection, renal cyst ruptured
Stomatitis Cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort,
oropharyngeal pain, stomatitis
Thrombocytopenia Platelet count decreased, thrombocytopenia
Upper respiratory infection Laryngitis, nasopharyngitis, pharyngitis, rhinitis, upper respiratory tract infection
Vision disorder Chromatopsia, diplopia, halo vision, photophobia, photopsia, vision blurred, visual acuity reduced, visual brightness,
visual impairment, visual perseveration, vitreous floaters
Visual loss Amaurosis, amaurosis fugax, blindness, blindness cortical, blindness day, blindness transient, blindness unilateral,
hemianopia, hemianopia heteronymous, hemianopia homonymous, night blindness, optic atrophy, optic nerve
disorder, optic neuropathy, optic ischemic neuropathy, retinopathy, quadrantanopia, sudden visual loss, toxic optic
neuropathy, tunnel vision, visual cortex atrophy, visual field defect, visual pathway disorder

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