Crizotinib cncr28040 cncr_28040

Original Article

Heart Rate Decrease During Crizotinib Treatment and Potential
Correlation to Clinical Response
Sai-Hong Ignatius Ou, MD, PhD1; Wilson P. Tong, MD1; Michele Azada, MPH1; Christina Siwak-Tapp, PhD1;
Joni Dy, RN, OCN1; and Jonathan A. Stiber, MD2

BACKGROUND: Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung
cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB,
patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and
clinical response to crizotinib. METHODS: A retrospective chart review was conducted of the timing and frequency of SB, patient
characteristics, and clinical response of patients to crizotinib treatment. RESULTS: Forty-twp patients who had ALK-rearranged or
mesenchymal epithelial transition (MET)-amplified NSCLC and received treatment with oral crizotinib 250 mg twice daily who were
enrolled in 2 crizotinib trials (PROFILE 1001 and PROFILE 1005) were analyzed. There was an average decrease of 26.1 beats per mi-
nute (bpm) from the pretreatment HR among all patients during crizotinib treatment. Twenty-nine patients (69%) experienced at
least 1 episode of SB (HR, <60 bpm). The average time to the lowest HR recorded was 18.6 weeks (range, 5-72 weeks). Patients who
experienced SB were significantly older (aged 55.8 years vs 47.8 years; P ¼ .0336), had a lower pretreatment HR (mean, 77.9 bpm vs
100.6 bpm; P ¼ .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P ¼ .0050) than patients who did not experience SB.
The overall response rate (P ¼ .0195) and the maximum tumor shrinkage (P ¼ .0205) were significantly greater in patients who expe-
rienced SB. CONCLUSIONS: HR decrease is common during crizotinib treatment. It remains to be determined whether the correlation
between HR decrease and clinical response to crizotinib reflects a biomarker of drug efficacy or a time/cumulative dose-dependent
C
phenomenon. Cancer 2013;000:000–000. V 2013 American Cancer Society.

KEYWORDS: crizotinib, sinus bradycardia, heart rate decrease, pharmacodynamic, receptor tyrosine kinase inhibitor, anaplastic
lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer.

INTRODUCTION
Crizotinib is a first-in-class, orally available anaplastic kinase (ALK) inhibitor that has exhibited impressive clinical activity
in ALK-rearranged nonsmall cell lung cancer (NSCLC) in 2 phase 2, single-arm clinical trials.1-3 It has also demonstrated
significantly improved progression-free survival (PFS) over single-agent chemotherapy as second-line treatment for
patients with ALK-rearranged NSCLC in a randomized phase 3 trial.4 Crizotinib has been approved in many countries for
the treatment of ALK-rearranged NSCLC. In addition, as a multitargeted receptor tyrosine kinase (RTK) inhibitor that
also can inhibit both the mesenchymal epithelial transition (MET) and ROS1 receptor tyrosine kinases, crizotinib has
demonstrated clinical activity in MET-amplified NSCLC and ROS1-rearranged NSCLC.5,6 Thus, crizotinib will likely
play an expanding role in targeted therapy for NSCLC.
Crizotinib is generally well tolerated, and most of its side effects are in the grade 1 and 2 range. The common side
effects reported are transient visual disorders and gastrointestinal upset (nausea, vomiting, diarrhea, or constipation).1-4 It
has also been reported that there was an average 2.5-beats per minute (bpm) decrease in the heart rate (HR) with every
100-ng/mL increase of serum crizotinib concentration.7 Indeed, according to the crizotinib package insert, grade 1 and 2
sinus bradycardia (SB) occurred in 5% of patients.8
We have observed many patients who had a reduction in their HRs while receiving crizotinib treatment, and a few
patients developed asymptomatic SB with an HR <45 bpm.9 This observation led us to perform a retrospective analysis
investigating the frequency, timing, and patient characteristics associated with SB during crizotinib treatment. In addition,
we performed an exploratory analysis of a potential correlation between HR changes and response to crizotinib.

Corresponding author: Sai-Hong Ignatius Ou, MD, PhD, Health Science Associate Clinical Professor, Chao Family Comprehensive Cancer Center, Department of
Medicine-Hematology/Oncology, University of California School of Medicine, 101 City Drive, Building 56, RT81, Room 241, Orange, CA 92868; Fax: (714) 456-2242;
ignatius.ou@uci.edu
1
Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, California; 2Division of Cardiology, Department of Medicine,
Duke University School of Medicine, Durham, North Carolina

DOI: 10.1002/cncr.28040, Received: December 20, 2012; Revised: February 4, 2013; Accepted: February 8, 2013, Published online in Wiley
Online Library (wileyonlinelibrary.com)

Cancer Month 00, 2013 1

Original Article

MATERIALS AND METHODS from all patients who experienced an HR <60 bpm.
Patients ECGs were obtained at every clinic visit if the HR was
Patients with ALK-rearranged or MET-amplified NSCLC 45 bpm for patients with profound SB even if they
who were enrolled in the molecular expansion cohort of reported no symptoms after initial clinic visits. These
the PROFILE 1001 trial (National Clinical Trial [NCT] ECGs were not mandated by the protocols but were
00585195) and the PROFILE 1005 trial obtained as part of the treatment monitoring as we
(NCT00932451) at the University of California Irvine observed that more patients experienced symptomatic SB.
Medical Center were identified and analyzed. The main The pretreatment HR, the lowest HR achieved during
eligibility criteria for both trials were aged 18 years, treatment, the time to maximum HR decrease, vital signs
stage IV ALK-rearranged NSCLC, and performance sta- (including blood pressure readings), and potential symp-
tus from 0 to 2. PROFILE 1001 allows any line of prior toms related to SB all were abstracted from clinic charts.
therapy, whereas PROFILE 1005 requires patients to fail Tumor Response
at least 1 prior line of platinum-based chemotherapy. RECIST version 1.0 was used to measure response in
ALK rearrangement was detected by break-apart fluores- PROFILE 8081001, and version 1.1 was used for PRO-
cence in sit hybridization, as described previously.1 MET FILE 1005. The maximum decrease in tumor measure-
amplification was determined by FISH, and MET/chro- ment from the pretreatment baseline level was obtained
mosome enumeration probe 7 (CEP7) values 2.2 were from clinic chart. A complete response (CR), a partial
considered amplified, as previously reported.5 Clinico- response (PR), stable disease (SD), and progressive disease
pathologic characteristics of the patients were reviewed, (PD) were defined according to RECIST.
including age at diagnosis, sex, disease stage, smoking his-
tory, histology, number of prior regimens, performance Statistical Analysis
status, tumor response, degree of tumor shrinkage, pre- Statistical analysis was performed using the SAS statistical
treatment HR, and lowest HR achieved. Concomitant software package (version 9.2; SAS Institute, Inc., Cary,
medications including, beta-blockers and calcium channel NC). Chi-square analysis was used to test dichotomous
blockers, were reviewed. For patients enrolled in PRO- variables, and the Student t test was used for continuous
FILE 1001, disease assessment was performed every 8 variables. Statistical differences were considered signifi-
weeks (2 cycles), whereas disease was assessed every 6 cant when P values were .05.
weeks (2 cycles) for patients enrolled in PROFILE 1005.
Clinic visits were every cycle for the first 15 cycles and RESULTS
then every 2 cycles thereafter for both trials. All patients Patient Characteristics Overall and According to
received crizotinib 250 mg twice daily. Both trials allowed Sinus Bradycardia or No Sinus Bradycardia
continuation of crizotinib beyond progression according Experienced
to Response Evaluation Criteria in Solid Tumors Forty-two patients (30 from PROFILE 1001 and 12 from
(RECIST) if there was ‘‘clinical benefit,’’ as determined by PROFILE 1005) were analyzed. None of the patients
the investigators. Common Terminology Criteria for were on any calcium channel blockers or beta-blockers
Adverse Event (CTCAE) version 3.0 was used to grade during crizotinib treatment. The first patient was started
adverse events. The data cutoff date was February 28, on oral crizotinib 250 mg twice daily on November 17,
2012. All patients signed informed consent. The PRO- 2008, and the last patients started crizotinib on June 6,
FILE 1001 and 1005 trials both were approved by the 2011. The mean follow-up for all patients was 48 weeks
University of California Irvine Institutional Review Board. (median, 42 weeks, 95% confidence interval, 4-116
weeks). Twenty-three patients still were receiving crizoti-
Heart Rate Changes nib treatment at the time of data cutoff. All patients had
CTCAE version 3 was used for both PROFILE 1001 and adenocarcinoma histology. None of the patients had dose
1005. SB was defined as an HR 60 bpm. We defined reduction during crizotinib treatment. The clinicopatho-
‘‘profound’’ SB as an HR 50 bpm. We chose this cutoff logic variables of all the patients are listed in Table 1.
level, because an HR 50 bpm is generally considered by There was a significant difference in the mean age at diag-
cardiologist the point at which patients potentially can ex- nosis between patients who did and did not experience SB
perience SB symptoms, such as dizziness or syncope. All (P ¼ .0366) (Table 1). There was a statistically significant
patients had pretreatment electrocardiograms (ECGs), as difference in performance status between patients who
mandated by both clinical trials. ECGs were obtained did and did not experience SB (P ¼ .0337), and 82.8% of

2 Cancer Month 00, 2013

Crizotinib and Heart Rate Changes/Ou et al

TABLE 1. Clinicopathologic Variables and Characteristics of Heart Rate Changes in 42 Patients Who Had
ALK-Rearranged or MET-Amplified, Crizotinib-Treated Nonsmall Cell Lung Cancer Stratified by Those
With and Without Sinus Bradycardia
No. of Patients (%)

Clinical Variable Total, N ¼ 42 SB, N ¼ 29 No SB, N ¼ 13 P

Patient characteristic
Age, y
Mean 53.3 55.8 47.8
Median [range] 51.0 [32-80] 52.0 [32-80] 48.0 [39-57] .0336
Sex
Men 24 (57.1) 17 (58.6) 7 (53.9)
Women 18 (42.9) 12 (41.4) 6 (46.1) .7725
Ethnicity
Caucasian 27 (64.3) 19 (65.5) 8 (61.5)
Asian 8 (19) 5 (17.2) 3 (23.1)
Hispanic 6 (14.3) 4 (13.8) 2 (15.4)
African American 1 (2.4) 1 (3.4) 1 (7.7) .8856
Performance status
0 30 (71.4) 24 (82.8) 6 (46.2)
1 11 (26.2) 5 (17.2) 6 (46.2)
2 1 (2.4) 0 (0) 1 (7.7) .0337
Smoking status
Never-smoker 38 (90.4) 26 (89.7) 12 (92.3)
Former/current smoker 4 (9.6) 3 (10.3) 1 (7.7) .6678
Molecular alterations
ALK-rearranged 41 (97.6) 28 (96.6) 13 (100)
MET-amplified 1 (2.4) 1 (3.4) 0 (0) .9917
No. of previous regimens
0-1 26 (61.9) 20 (69) 6 (46.2) .3289
2 16 (38.1) 9 (31) 7 (53.8)
HR changes
Mean pretreatment HR, bpm 84.9 77.9 100.6
Median [95% CI] 83 [60-115] 74 [61-103] 100 [80-137] .0002
Mean lowest HR achieved, bpm 58.8 49.9 78.5
Median [95% CI] 54 [40-95] 52 [40-59] 75 [62-137] .0001
Mean maximum HR decrease, bpm 26.1 27.9 22.1
Median [95% CI] 26) [4-52] 27 [11-56] 24 [0-38] .3685
Mean time to maximum HR decrease, wk 18.6 24.1 6.5
Median [95% CI] 9.5 [5-72] 14 [3-80] 6 [0-17] .0089
Mean duration of treatment, wks 44.1 52.9 24.6
Median [95% CI] 28 [5-100] 44 [9-110] 19 [1-92] .0050
Mean duration of response, wks 36.1 36.6 34.9
Median [95% CI] 26 [7-88] 27 [7-85] 21 [5-99] .5222

Abbreviations: AKL, anaplastic lymphoma kinase; bpm, beats per minute; CI, confidence interval; HR, heart rate; MET, mesenchymal epithelial transition; SB,
sinus bradycardia.

patients who experienced SB, compared with only 46.2% experienced at least 1 episode of SB (HR, 60). The
of patients who did not experience SB, had a pretreatment mean maximum decrease in HR for all patients was
performance status of 0 (Table 1). There was no difference 26.1 bpm (Table 1). There was a significant differ-
between patients who did and did not experience SB ence in the pretreatment HR (P ¼ .0002), the mean
according to sex (P ¼ .7725), race (P ¼ .8856), smoking lowest HR achieved (P .0001), and the mean time
status (P ¼ .6678), or the number of prior regimens (P ¼ to lowest HR recorded (P ¼ .0089) between patients
.3298) (Table 1). who did and did not experience SB (Table 1). It is
Heart Rate Changes Among All Patients and noteworthy that there was no difference between the
According to Sinus Bradycardia or No mean decrease in HR between patients who did and
Sinus Bradycardia Experienced did not experience SB (P ¼ .3685) (Table 1). There
Thirty-eight patients (90.4%) experienced at least 1 was a significant difference in the time to lowest HR
episode of an absolute decrease in HR of 10 bpm recorded between patients who did and did not expe-
from pretreatment baseline. Twenty-nine patients (69) rience SB (P ¼ .0089) (Table 1).


Original Article

TABLE 2. Heart Rate Variables in Patients Without Sinus Bradycardia, With Sinus Bradycardia, and With
Profound Sinus Bradycardia

HR Changes No SB, N ¼ 13 SB, N ¼ 15 Profound SB, N ¼ 14 P

Mean pretreatment HR, bpm 100.6 81.5 74.0
Median (95% CI) 100.0 (80-137) 82.0 (60-115) 70.5 (61-103) .0003
Mean lowest HR recorded, bpm 78.5 55.0 44.5
Median (95% CI) 75.0 (62-137) 55.0 (52-59) 44.5 (39-51) .0001
Mean time to maximum HR decrease, wk 6.5 18.7 29.9
Median (95% CI) 6.0 (0-17) 14.0 (3-80) 14.5 (2-120) .0261
Mean maximum HR decrease, bpm 22.1 26.5 29.5
Median (95% CI) 24.0 (0-38) 30.0 (4-56) 26.0 (11-63) .5695
Mean treatment duration, wk 24.6 47.7 58.4
Median (95% CI) 19.0 (1-92) 44.0 (8-116) 59.5 (9-110) .0165
Mean response duration, wk 34.9 34.9 38.4
Median (95% CI) 21.0 (5-99) 27.0 (5-88) 30.5 (7-85) .7292

Abbreviations: bpm, beats per minute; CI, confidence interval; HR, heart rate; SB, sinus bradycardia.

TABLE 3. Clinical Response of the 42 Patients With ALK-Rearranged or MET-Amplified, Crizotinib-Treated
Nonsmall Cell Lung Cancer Stratified According to Those With and Without Sinus Bradycardia

Patient Total No. of Patients,
Characteristics N 42 SB, N 29 No SB, N 31 P

All patients
Best response to crizotinib: No. (%)
CR 3 (7.1) 3 (10.3) 0 (0)
PR 18 (42.9) 15 (51.7) 3 (23.1)
SD 18 (42.9) 10 (34.5) 8 (61.5)
PD 1 (2.4) 1 (3.4) 0 (0)
Not evaluable 2 (4.8) 0 (0) 2 (15.4) .0496
ORR: CR þ PR, % 50 62.1 23.1 .0195
DCR: CR þ PR þ SD, % 92.9 96.6 84.6 .1650
Mean maximum decrease in cumulative tumor 38.4 45.4 22.8
measurement from baseline for all patients, %
Median [95% CI] 35.5 [0-80] 53 [0-80] 21 [0-65] .0205
Patients who achieved clinical benefit: CR þ PR þ SD
No. of patients 39 28 11
Mean maximum decrease in cumulative tumor 41.4 47 26.9
measurement from baseline for all patients, %
Median [95% CI] 39 [0-78] 53.5 [1-80] 29 [0-65] .0584

Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; PR, partial
response; SB, sinus bradycardia; SD, stable disease.

Profound Sinus Bradycardia (P .0001), or mean time to maximum HR decrease
Among the 29 patients who experienced SB, 13 patients (P ¼ .0261) among patients who experienced profound
(44.8%) experienced at least 1 episode of profound SB (HR, SB, SB, and no SB (Table 2). It is worth noting that,
50 bpm). There was no difference in sex (P ¼ .9476), again, there was no statistically significance difference in
race (P ¼ .7791), performance status (P ¼ .1411), or the the average maximum HR decrease among patients who
number of prior regimens (P ¼ .0902) among patients who experienced profound SB, SB, and no SB (P ¼ .5695)
experienced profound SB, SB, or no SB. Although there also (Table 2). None of the patients who experienced SB or
was no difference in the age of diagnosis among the 3 profound SB were symptomatic or had ECG changes,
such as PR or QTc prolongation.
groups, the patients who experienced profound SB had the
oldest median age of diagnosis at 58.7 years followed by age Clinical Response and Tumor Shrinkage
53.1 years for patients who experienced SB only and age The overall response rate was significantly higher among
47.8 years for patients who experienced no SB (P ¼ .0671). patients who experienced SB than patients who experi-
There was a significant difference in the pretreat- enced no SB (P ¼ .0195) (Table 3). The mean maximum
ment HR (P ¼ .0003), the mean lowest HR recorded decrease in cumulative tumor measurement from baseline



TABLE 4. Clinical Response of Patients Who Had Crizotinib-Treated Nonsmall Cell Lung Cancer Without
Sinus Bradycardia, With Sinus Bradycardia, and With Profound Sinus Bradycardia

Clinical Response No SB, N ¼ 13 SB, N ¼ 15 Profound SB, N ¼ 14 P

All patients
Best response to crizotinib: No. (%)a
CR 0 (0) 1 (6.7) 2 (14.3)
PR 3 (23.1) 7 (46.7) 8 (57.1)
SD 8 (61.5) 6 (40) 4 (28.6)
PD 0 (0) 1 (6.7) 0 (0)
Not evaluable 2 (15.4) 0 (0) 0 (0) .1579
ORR: CR þ PR, % 23.1 53.3 71.4 .0406
DCR: CR þ PR þ SD, % 84.6 93.3 100 .2992
Mean maximum decrease in tumor measurement, % 22.8 40.5 50.6
Median [95% CI] 21 [0-65] 39 [0-80] 56 [0-100] .0447
Patients who achieved clinical benefit: CR þ PR þ SD
No. of patients 11 14 14
Mean maximum decrease in tumor measurement, % 26.9 43.4 50.6
Median [95% CI] 29 [0-65] 46 [1-80] 56 [0-100] .1171

Abbreviations: CR, complete response; DCR: disease control rate; ORR: overall response rate; PD: progressive disease; PR, partial response; SB, sinus brady-
cardia; SD, stable disease.
a
The best response was rated according to Response Evaluation Criteria in Solid Tumors (RECIST).

also was significantly higher among patients who experi- difference in the mean pretreatment HR between men
enced SB than those who did not (P ¼ .0205) (Table 3). and women (83.6 bpm vs 86.7 bpm, respectively; P ¼
When only considering patients who had achieved clinical .8189), the mean maximum decrease in HR recorded
benefit (complete responses þ partial responses þ stable (27.8 bpm vs 23.9 bpm, respectively; P ¼ .1814), the
disease), the maximum tumor shrinkage also was numeri- mean lowest HR achieved (55.8 bpm vs 62.8, respectively;
cally higher among patients who experienced SB than P ¼ .5330), or the mean time to the lowest HR recorded
among those who did not, although the difference was not (22.1 weeks vs 14.1 weeks, respectively; P ¼ .2684).
statistically significant (P ¼ .0584) (Table 3). In terms of clinical response to crizotinib, there was
Similarly, the overall response rate was highest among no difference in the overall response rate between men
patients who experienced profound SB, followed by and women (45.8% vs 55.6%, respectively; P ¼ .5329).
patients who experienced SB, and then patients who expe- Similarly, there was no difference in the average maxi-
rienced no SB (P ¼ .0406) (Table 4). This also was similar mum tumor decrease between men and women (35.8% vs
in patients who experienced profound SB, who had the 41.9%, respectively; P ¼ .4450).
greatest reduction in cumulative tumor measurement from
baseline, followed by patients who experienced SB, and DISCUSSION
then by patients who experienced no SB (P ¼ .0447) The major observation from this single-institution retro-
(Table 4). Again, when only the patients who achieved spective analysis of HR changes during crizotinib treat-
clinical benefit from crizotinib were included, the cumula- ment is that HR decrease is a common phenomenon
tive tumor reduction was numerically highest among during such treatment. HR decrease has been reported as
patients who experienced profound SB, although the dif- a pharmacodynamic phenomenon of crizotinib with an
ference was no longer significant (P ¼ .1171) (Table 4). average of 2.5 bpm decrease per 100 ng of crizotinib.7
The average pharmacokinetic level of crizotinib achieved
Heart Rate Changes and Clinical is approximately 280 ng/mL10; thus, the average HR
Response by Sex decrease should be approximately 8 bpm. We observed
There was no difference in the median age of diagnosis that 90% of patients who were receiving crizotinib had a
between men and women (men vs women: 53.9 years vs 1-time HR decrease 10 bpm. The average HR decrease
52.6 years, respectively; P ¼ .3597). There also was no for all patients was approximately 26.1 bpm but without
difference in the mean treatment duration between men any symptoms or ECG changes (such as PR or QTc pro-
and women (50.5 weeks vs 35.7 weeks, respectively; P ¼ longation). The higher than expected HR decrease
.2970) or in the mean response duration (33.5 weeks vs observed in this report may reflect individual pharmacoki-
39.4 weeks, respectively; P ¼ .4841). There was no netic variation or autoinhibition of crizotinib, because


Original Article

crizotinib is a strong cytochrome P450, family 3, subfam- had HRs 45 bpm while on crizotinib all were graded as
ily A (CYP3A) inhibitor and also is itself metabolized by having grade 1 SB.9 In the future, we recommend incor-
CYP3A. porating specific ranges of the HR below 60 bpm in addi-
Our exploratory analysis also revealed that patients tion to symptoms experienced into the CTCAE grading
who experienced SB had a significantly higher response of SB to allow a better appreciation of the extent of the SB
rate and greater cumulative tumor shrinkage during crizo- by the oncology community.
tinib therapy, and patients who experience profound SB It has been demonstrated that crizotinib causes a
had the highest response rate and greatest cumulative tu- rapid but reversible drop in testosterone in men, which
mor shrinkage. Patients who experienced profound SB potentially may result in an HR decrease.11 Our analysis
also were on crizotinib treatment the longest. Thus, did not reveal any significant difference in the HR param-
although this observation raises the possibility of a positive eters examined and the clinical response to crizotinib
correlation between the magnitude of HR decrease and between men and women. Thus, decrease in testosterone
the extent of clinical benefit from crizotinib, it also may level is unlikely to be a mechanism that accounts for the
only reflect that the magnitude of HR decrease is a time- HR decrease associated with the receipt of crizotinib.
dependent or cumulative dose-dependent phenomenon. Another potential cause of HR decrease may be hypothyr-
Nevertheless, it points to the importance for oncologists oidism; however, we did not measure thyroid hormone
to try and avoid common medications that can cause HR levels in any of our patients, because none of our patients
lowering, such as beta-blockers and calcium channel exhibited any signs of hypothyroidism.
blockers, during the entire course of crizotinib treatment, The mechanism(s) that allow crizotinib to slow
because patients can continue to experience HR decrease down HR remain unknown. Given our observation that
well into the course of their crizotinib treatment. We want crizotinib lowers the HR without any drop in blood
to emphasize that most of our patients were not in perma- pressure, its effect on the heart is more likely to be chrono-
nent SB. Many of these patients alternated between tropic (which affects the sinoatrial lymph node) or dro-
normal sinus rhythm and SB during some of the subse- motropic (which affects the atrioventricular lymph node)
quent clinic visits. Only a few patients were in persistent rather than inotropic. Alternatively, the bradycardiac
SB during the majority of clinic visits. effect of crizotinib may be because of its anti-MET effects,
The second observation is that SB from crizotinib is because an analysis of tivantinib, another MET inhibitor,
more a reflection of the pretreatment HR rather than a also revealed HR decreases (Lee Rosen, University of Cali-
true adverse event per se. We observed that the HR before fornia Los Angeles, personal communications).
patients received crizotinib treatment was significantly With all of the limitations of this report, including
higher among patients who did not experience SB than its retrospective nature, the limited number of patients an-
among those who experienced SB, whereas there was no alyzed, and the recording of the HR at irregularly spaced
statistically significant difference in the average maximum intervals, depending on scheduled protocol visits, which
HR decrease between these patient groups. We also varied and became less frequent with prolonged crizotinib
observed that older patients and patients with good per- treatment, it still represents the largest study to date
formance status (conditions that are generally associated describing HR changes during crizotinib treatment and
with slower HR) were significantly more likely to experi- exploring the potential relation between HR changes and
ence SB while on crizotinib. clinical response to crizotinib. Furthermore, the data from
Neither CTCAE version 3 nor the newer version 4.0 this study have undergone extensive queries and quality-
specifies the HR at which it is considered SB. It is gener- control by the clinical trial sponsor (Pfizer Inc., Groton,
ally defined in cardiology that bradycardia occurs at an Conn), because they are part of the data submission to the
HR 60 bpm. However, an oncologist following a US Food and Drug Administration in support the orphan
patient with ALK-rearranged NSCLC who is deriving drug application and eventual approval of crizotinib in
clinical benefit from crizotinib and is asymptomatic may the United States. Our exploratory analysis of a positive
not consider an HR 59 bpm significant. Because correlation of the magnitude of HR decrease with clinical
CTCAE grades the severity of SB by the presence or response and tumor shrinkage should be considered only
absence of symptoms rather than by the actual lowest as hypothesis-generating. The PROFILE 1005 study has
recorded HR, we may not appreciate the extent of HR now enrolled more than 1000 patients with ALK-rear-
decrease while reading the oncology literature. For exam- ranged NSCLC and may provide a much more robust
ple, our 3 previously reported asymptomatic patients who analysis of the frequency of, timing, patient characteristics



associated with, and potential correlation to clinical 5. Ou S-HI, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib
(PF02341066), a dual mesenchymal-epithelial transition (MET)
response with HR changes during crizotinib treatment. and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small
cell lung cancer patient with de novo MET amplification. J Thorac
FUNDING SOURCES Oncol. 2011;6:942-946.
6. Shaw AT, Camidge DR, Engelman JA, et al. Clinical activity of cri-
The PROFILE 1001 and 1005 trials were both funded by zotinib in advanced non-small cell lung cancer (NSCLC) harboring
Pfizer. ROS1 gene rearrangement [abstract]. J Clin Oncol. 2012;30S.
Abstract 7508.
7. Nickens D, Tan W, Wilner K, et al. Pharmacokinetic/pharmacody-
CONFLICT OF INTEREST DISCLOSURES namic evaluation of the concentration-QTc relationship of crizoti-
Sai-Hong I. Ou has received honorarium from Pfizer. nib (PF-02341066), an anaplastic lymphoma kinase and c-MET/
hepatocyte growth factor receptor dual inhibitor administered orally
to patients with advanced cancer [abstract 1673]. Poster presented
at: 101st Annual Meeting of the American Association for Cancer
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